Methods and compositions to enhance bone growth comprising a statin

ABSTRACT

Implantable medical devices and methods are provided that have one or more statins disposed therein. The medical devices may be implanted at near or in a bone defect to enhance bone growth. In some embodiments, the medical device provided allows for sustain release of the statin and facilitates bone formation and repair of the fracture site.

This application claims the benefit of the filing date of U.S.Provisional Patent Application Ser. No. 61/493,749, filed on Jun. 6,2011. This entire disclosure is hereby incorporated by reference intothe present disclosure.

BACKGROUND

Bone is a composite material that is composed of impure hydroxyapatite,collagen and a variety of non-collagenous proteins, as well as embeddedand adherent cells. Due to disease, a congenital defect or an accident,a person may lose or be missing part or all of one or more bones orregions of cartilage in his or her body, and/or have improper growth orformation of bone and/or cartilage.

Mammalian bone tissue is known to contain one or more proteinaceousmaterials that are active during growth and natural bone healing. Thesematerials can induce a developmental cascade of cellular events thatresult in bone formation. Typically, the developmental cascade of boneformation involves chemotaxis of mesenchymal cells, proliferation ofprogenitor cells, differentiation of cartilage, vascular invasion, boneformation, remodeling and marrow differentiation.

When bone is damaged, often bone grafting procedures are performed torepair the damaged bone especially in cases where the damage is complex,poses a significant risk to the patient, and/or fails to heal properly.Bone grafting is also used to help fusion between vertebrae, correctdeformities, or provide structural support for fractures of the spine.In addition to fracture repair, bone grafting is also used to repairdefects in bone caused by birth defects, traumatic injury, or surgeryfor bone cancer.

There are at least three ways in which a bone graft can help repair adefect. The first is called osteogenesis, the formation of new bonewithin the graft. The second is osteoinduction, a process in whichmolecules contained within the graft (e.g., bone morphogenic proteins)convert the patient's cells into cells that are capable of forming bone.The third is osteoconduction, a physical effect by which a medicaldevice (e.g., matrix) often containing graft material acts as a scaffoldon which bone and cells in the recipient are able to form new bone.

The source of bone for grafting can be obtained from bones in thepatient's own body (e.g., hip, skull, ribs, etc.), called autograft, orfrom bone taken from other people that is frozen and stored in tissuebanks, called allograft. The source of bone may also be derived fromanimals of a different species called a xenograft.

Some grafting procedures utilize a variety of natural and syntheticmedical devices (e.g., matrices, depots, etc.) with or instead of bone(e.g., collagen, synthetic biodegradable depots, acrylics,hydroxyapatite, calcium sulfate, ceramics, etc.). To place the medicaldevice at the bone defect, the surgeon makes an incision in the skinover the bone defect and places the matrix at, near, or into the defect.

As persons of ordinary skill are aware, growth factors (e.g., bonemorphogenic protein-2) may be placed on the medical device in order tospur the patient's body to begin the formation of new bone and/orcartilage. These growth factors act much like a catalyst, encouragingthe necessary cells (including, but not limited to, mesenchymal stemcells, osteoblasts, and osteoclasts) to more rapidly migrate into themedical device, which is eventually resorbed via a cell-mediated processand newly formed bone is deposited at or near the bone defect. In thismanner severe fractures may be healed, and vertebrae successfully fused.Unfortunately, many growth factors tend to be very expensive andincrease the cost of bone repair.

One class of molecules known to the medical profession are statins.Statins are a family of molecules sharing the capacity to competitivelyinhibit the hepatic enzyme 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase. This enzyme catalyses the rate-limiting step in theL-mevalonate pathway for cholesterol synthesis. Oral statin use blockscholesterol synthesis and is effective in treating hypercholesterolemia,hyperlipidemia and arteriosclerosis. In recent years, oral statins havebeen shown to reduce cardiovascular-related morbidity and mortality inpatients with and without coronary disease.

To date, locally delivered medical devices containing statins have notbeen appreciated as providing a stable microenvironment that facilitatesbone growth, particularly when used in bone defects, fractures and/orvoids. Thus, there is a need to develop new medical devices that improverepair of bone defect, voids and/or fractures.

SUMMARY

In some embodiments, implantable medical devices and methods areprovided that retain the statin at, near or in the bone defect (e.g.,fracture, void, etc.) to facilitate healing of the bone defect and avoidadverse local tissue reactions to the statin. In some embodiments, theimplantable medical devices provided are osteoconductive and allow gapsand fractures to be filled with new bridging bone faster. All of whichleads to a reduced time for healing. In some embodiments, theimplantable medical devices and methods provided are easy and lesscostly to manufacture because the active ingredient is a small moleculestatin, as opposed to a larger, and, sometimes, more expensive and lessstable growth factor.

In one embodiment, the implantable medical devices and methods alloweasy delivery to the bone defect (e.g., fracture site, synovial joint,at or near the spinal column, etc.) using a gel that hardens uponcontact with the target tissue. In this way, accurate and preciseimplantation of the medical device in a minimally invasive procedure canbe accomplished. In another embodiment, there is an implantable medicaldevice configured to fit at, near or in a bone defect, the medicaldevice comprising a biodegradable polymer and a therapeuticallyeffective amount of a statin disposed throughout the medical device,wherein the medical device allows influx of at least progenitor, and/orbone cells at, near or in the bone defect.

In yet another embodiment, there is a method of treating a bone defectin which the bone defect site possesses at least one cavity, the methodcomprising inserting an implantable medical device at, near or in thedefect site, the implantable medical device comprising a biodegradablepolymer and a therapeutically effective amount of a statin disposedthroughout the medical device, wherein the medical device allows influxof at least progenitor, and/or bone cells at, near or in the bonedefect.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE FIGURES

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a front view of a joint capsule showing percutaneousinjections of the medical device (a gel containing a statin) into oraround a hematoma at an early stage of fracture healing in long bones.

FIG. 2 illustrates a front view of a joint capsule showing implantationof a plurality of solid biodegradable depots containing a statin intothe bone defect (a gap between fractured bones) at the early stage offracture healing in long bones.

FIG. 3 is a bar graph illustration of the percentage increase in maximalload to rat femoral fractures for different formulations of lovastatincompared to a control that did not contain lovastatin.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present application. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations; the numericalvalues are as precise as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.Moreover, all ranges disclosed herein are to be understood to encompassany and all subranges subsumed therein. For example, a range of “1 to10” includes any and all subranges between (and including) the minimumvalue of 1 and the maximum value of 10, that is, any and all subrangeshaving a minimum value of equal to or greater than 1 and a maximum valueof equal to or less than 10, e.g., 5.5 to 10.

Additionally, unless defined otherwise or apparent from context, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

Unless explicitly stated or apparent from context, the following termsor phrases have the definitions provided below:

DEFINITIONS

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a medical device” includes one, two, three or more medicaldevices.

The term “implantable” as utilized herein refers to a biocompatiblemedical device (e.g., matrix, drug depot, etc.) retaining potential forsuccessful placement within a mammal. The expression “implantablemedical device” and expressions of the like import as utilized hereinrefers to an object implantable through surgery, injection, or othersuitable means whose primary function is achieved either through itsphysical presence or mechanical properties.

The term “biodegradable” includes that all or parts of the medicaldevice will degrade over time by the action of enzymes, by hydrolyticaction and/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that a medical device (e.g.,matrix (e.g., sponge, sheet, etc.), depot, etc.) can break down ordegrade within the body to non-toxic components after or while atherapeutic agent has been or is being released. By “bioerodible” it ismeant that the medical device will erode or degrade over time due, atleast in part, to contact with substances found in the surroundingtissue, fluids or by cellular action. By “bioabsorbable” or“bioresorbable” it is meant that the medical device will be broken downand absorbed within the human body, for example, by a cell or tissue.“Biocompatible” means that the medical device will not cause substantialtissue irritation or necrosis at the target tissue site.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

The term “resorbable” includes biologic elimination of the products ofdegradation by metabolism and/or excretion over time, for example,usually months.

The term “particle” refers to pieces of a substance of all shapes,sizes, thickness and configuration such as fibers, threads, narrowstrips, thin sheets, clips, shards, etc., that possess regular,irregular or random geometries. It should be understood that somevariation in dimension will occur in the production of the particles andparticles demonstrating such variability in dimensions are within thescope of the present application.

The term “target tissue site” is intended to mean the location of thetissue to be treated. Typically the placement site of the medical devicewill be the same as the target site to provide for optimal targeted drugdelivery. However, the present application also contemplates positioningthe medical device at a placement site at, near or in the target sitesuch that the therapeutic agent (e.g., statin) can be delivered to thesurrounding vasculature, which carries the agent to the desired nearbytarget site. As used herein, the term “at or near” includes embodimentswhere the placement site and target site are within close proximity(e.g., within about 1 mm to 5 cm).

The term “autograft” as utilized herein refers to tissue intended forimplantation that is extracted from the intended recipient of theimplant.

The term “allograft” as utilized herein refers to tissue intended forimplantation that is taken from a different member of the same speciesas the intended recipient.

The term “xenogenic” as utilized herein refers to material intended forimplantation obtained from a donor source of a different species thanthe intended recipient. For example, when the implant is intended foruse in an animal such as a horse (equine), xenogenic tissue of, e.g.,bovine, porcine, caprine, etc., origin may be suitable.

The term “transgenic” as utilized herein refers to tissue intended forimplantation that is obtained from an organism that has been geneticallymodified to contain within its genome certain genetic sequences obtainedfrom the genome of a different species. The different species is usuallythe same species as the intended implant recipient but such limitationis merely included by way of example and is not intended to limit thedisclosure here in anyway whatsoever.

The expressions “whole bone” and “substantially fully mineralized bone”refer to bone containing its full or substantially full, originalmineral content that can be used. This type of bone can be used to makethe medical device.

The expression “demineralized bone” includes bone that has beenpartially, fully, segmentally or superficially (surface) demineralized.This type of bone can be used to make the medical device.

The expression “substantially fully demineralized bone” as utilizedherein refers to bone containing less than about 8% of its originalmineral context. This type of bone can be used to make the medicaldevice.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug (e.g., statin) results in alteration of thebiological activity, such as, for example, promotion of bone, cartilageand/or other tissue (e.g., vascular tissue) growth, inhibition ofinflammation, reduction or alleviation of pain, improvement in thecondition through inhibition of an immunologic response, etc. The dosageadministered to a patient can be as single or multiple doses dependingupon a variety of factors, including the drug's administeredpharmacokinetic properties, the route of administration, patientconditions and characteristics (sex, age, body weight, health, size,etc.), extent of symptoms, concurrent treatments, frequency of treatmentand the effect desired. In some embodiments, all or parts (e.g.,surfaces, regions, layers, etc.) of the medical device (e.g., drugdepot) may be designed for immediate release. In other embodiments themedical device (e.g., drug depot) may be designed for sustained release.In other embodiments, the medical device (e.g., drug depot) comprisesone or more immediate release surfaces, layers, regions and one or moresustained release surfaces layers or regions. In some embodiments theimplantable medical device is designed for burst release within 24 or 48hours. For example, in some embodiments, the drug depot comprises aninitial burst surface where 5% to about 10% by weight of the statin isreleased within 24 hours.

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The phrases “prolonged release”, “sustained release” or “sustainrelease” (also referred to as extended release or controlled release)are used herein to refer to one or more therapeutic agent(s) that isintroduced into the body of a human or other mammal and continuously orcontinually releases a stream of one or more therapeutic agents over apredetermined time period and at a therapeutic level sufficient toachieve a desired therapeutic effect throughout the predetermined timeperiod. Reference to a continuous or continual release stream isintended to encompass release that occurs as the result ofbiodegradation in vivo of the medical device and/or component thereof,or as the result of metabolic transformation or dissolution of thetherapeutic agent(s) or conjugates of therapeutic agent(s). The releaseneed not be linear and can be pulse type dosing.

In some embodiments, the medical device comprises a matrix. The “matrix”of the present application is utilized as a scaffold for bone and/orcartilage repair, regeneration, and/or augmentation. Typically, thematrix provides a 3-D matrix of interconnecting pores, which acts as ascaffold for cell migration. The morphology of the matrix guides cellmigration and cells are able to migrate into or over the matrix,respectively. The cells then are able to proliferate and synthesize newtissue and form bone and/or cartilage. In some embodiments, the matrixis resorbable.

In some embodiments, the matrix can be malleable, cohesive, followableand/or can be shaped into any shape. The term “malleable” includes thatthe matrix is capable of being permanently converted from a first shapeto a second shape by the application of pressure.

The term “cohesive” as used herein means that the putty tends to remaina singular, connected mass upon movement, including the exhibition ofthe ability to elongate substantially without breaking upon stretching.

The term “flowable” refers to a characteristic of a material whereby,after it is hydrated, it can be passed through a conduit, such as acannula or needle, by exerting a hydraulic pressure in the conduit.

The term “injectable” includes that the material can be placed at thetarget tissue site by extrusion of such material from the end of acannula, needle, tube, orifice, or the like.

The term “shape-retaining” includes that the matrix (e.g., putty,flowable material, paste, etc.) is highly viscous and unless acted uponwith pressure tends to remain in the shape in which it is placed.

The term “shaped” includes that the matrix can be molded by hand ormachine or injected in the target tissue site (e.g., bone defect,fracture, or void) in to a wide variety of configurations. In someembodiments, the matrix can be formed into sheets, blocks, rings,struts, plates, disks, cones, pins, screws, tubes, teeth, bones, portionof bone, wedges, cylinders, threaded cylinders, or the like, as well asmore complex geometric configurations.

A “drug depot” is the composition in which the statin is administered tothe target tissue site. Thus, a drug depot may comprise a physicalstructure to facilitate implantation and retention in a desired site(e.g., bone void, fracture site, osteoporosis bone, etc.). The drugdepot may also comprise the drug itself. The term “drug” as used hereinis generally meant to refer to any substance that alters the physiologyof a patient. The term “drug” may be used interchangeably herein withthe terms “therapeutic agent,” “therapeutically effective amount,” and“active pharmaceutical ingredient” or “API.” It will be understood thatunless otherwise specified a “drug” formulation may include more thanone therapeutic agent, wherein exemplary combinations of therapeuticagents include a combination of two or more drugs. The drug provides aconcentration gradient of the therapeutic agent for delivery to thesite. In various embodiments, the drug depot provides an optimal drugconcentration gradient of the therapeutic agent at a distance of up toabout 0.01 cm to about 20 cm from the administration site and comprisesthe statin.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical deliverycompositions. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

In various embodiments, the medical device (e.g., matrix, drug depot,etc.) can be designed to cause an initial burst dose of the statinwithin the first twenty-four or forty-eight hours after implantation.“Initial burst” or “burst effect” or “bolus dose” refers to the releaseof therapeutic agent from the medical device (e.g., one or moresurfaces, regions or layers of the drug depot) during the firsttwenty-four hours, or forty-eight hours after the device comes incontact with an aqueous fluid (e.g., synovial fluid, cerebral spinalfluid, saline, blood etc.). In some embodiments, the medical device(e.g., weight of the drug depot) releases 5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50% of the total weight of the statin loaded in themedical device within the first twenty-four, or forty-eight hours afterimplantation when the device comes into contact with bodily fluid. The“burst effect” or “bolus dose” is believed to be due to the increasedrelease of therapeutic agent from the device (e.g., drug depot). Inalternative embodiments, the medical device (e.g., drug depot) isdesigned to avoid or reduce this initial burst effect (e.g., by applyingan outer polymer coating to the depot or imbedding drug deep within thepolymer, or using a polymer having a high molecular weight orcombinations thereof, etc.).

The terms “treating” and “treatment” when used in connection with adisease or condition refer to executing a protocol that may include arepair procedure (e.g., closed fracture repair procedure), administeringone or more matrices to a patient (human or other mammal), in an effortto alleviate signs or symptoms of the disease or condition orimmunological response. Alleviation can occur prior to signs or symptomsof the disease or condition appearing, as well as after theirappearance. Thus, treating or treatment includes preventing orprevention of disease or undesirable condition. In addition, treating,treatment, preventing or prevention do not require complete alleviationof signs or symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient.

The medical device may be osteogenic. The term “osteogenic” as usedherein includes the ability of the medical device (e.g., matrix, drugdepot, etc.) to enhance or accelerate the growth of new bone tissue byone or more mechanisms such as osteogenesis, osteoconduction and orosteoinduction.

The medical device may be osteoinductive. The term “osteoinductive” asused herein includes the ability of a substance to recruit cells fromthe host that have the potential for forming new bone and repairing bonetissue. Most osteoinductive materials can stimulate the formation ofectopic bone in soft tissue.

In some embodiments, the medical device is osteoconductive and can bedelivered to other surgical sites, particularly sites at which bonegrowth is desired. These include, for instance, the repair of spine(e.g., vertebrae fusion) cranial defects, iliac crest back-filling,acetabular defects, in the repair of tibial plateau, long bone defects,spinal site defects or the like. Such methods can be used to treat majoror minor defects in these or other bones caused by trauma (includingopen and closed fractures), disease, or congenital defects, for example.The term “osteoconductive” as utilized herein includes the ability of anon-osteoinductive substance to serve as a suitable template orsubstrate along which bone may grow.

The medical device may be configured for the repair of a simplefracture, compound fracture or non-union; as an external fixation deviceor internal fixation device; for joint reconstruction, arthrodesis,arthroplasty or cup arthroplasty of the hip; for femoral or humeral headreplacement; for femoral head surface replacement or total jointreplacement; for repair of the vertebral column, spinal fusion orinternal vertebral fixation; for tumor surgery; for deficit filling; fordiscectomy; for laminectomy; for excision of spinal cord tumors; for ananterior cervical or thoracic operation; for the repairs of a spinalinjury; for scoliosis, for lordosis or kyphosis treatment; forintermaxillary fixation of a fracture; for mentoplasty; fortemporomandibular joint replacement; for alveolar ridge augmentation andreconstruction; as an inlay osteoimplant; for implant placement andrevision; for sinus lift; for a cosmetic procedure; and, for the repairor replacement of the ethmoid, frontal, nasal, occipital, parietal,temporal, mandible, maxilla, zygomatic, cervical vertebra, thoracicvertebra, lumbar vertebra, sacrum, rib, sternum, clavicle, scapula,humerus, radius, ulna, carpal bones, metacarpal bones, phalanges, ilium,ischium, pubis, femur, tibia, fibula, patella, calcaneus, tarsal bonesor metatarsal bones, or osteoporosis treatment.

The medical device may include a carrier. The term “carrier” includes adiluent, adjuvant, buffer, excipient, or vehicle with which acomposition can be administered. Carriers can include sterile liquids,such as, for example, water and oils, including oils of petroleum,animal, vegetable or synthetic origin, such as, for example, peanut oil,soybean oil, mineral oil, sesame oil, or the like. The statin mayinclude a carrier.

The term “excipient” includes a non-therapeutic agent added to themedical device to provide a desired consistency or stabilizing effect.Excipients for parenteral formulations, include, for example, oils(e.g., canola, cottonseed, peanut, safflower, sesame, soybean), fattyacids and salts and esters thereof (e.g., oleic acid, stearic acid,palmitic acid), alcohols (e.g., ethanol, benzyl alcohol), polyalcohols(e.g., glycerol, propylene glycols and polyethylene glycols, e.g., PEG3350), polysorbates (e.g., polysorbate 20, polysorbate 80), gelatin,albumin (e.g., human serum albumin), salts (e.g., sodium chloride),succinic acid and salts thereof (e.g., sodium succinate), amino acidsand salts thereof (e.g., alanine, histidine, glycine, arginine, lysine),acetic acid or a salt or ester thereof (e.g., sodium acetate, ammoniumacetate), citric acid and salts thereof (e.g., sodium citrate), benzoicacid and salts thereof, phosphoric acid and salts thereof (e.g.,monobasic sodium phosphate, dibasic sodium phosphate), lactic acid andsalts thereof, polylactic acid, glutamic acid and salts thereof (e.g.,sodium glutamate), calcium and salts thereof (e.g., CaCl₂, calciumacetate), phenol, sugars (e.g., glucose, sucrose, lactose, maltose,trehalose), erythritol, arabitol, isomalt, lactitol, maltitol, mannitol,sorbitol, xylitol, nonionic surfactants (e.g., TWEEN 20, TWEEN 80),ionic surfactants (e.g., sodium dodecyl sulfate), chlorobutanol, DMSO,sodium hydroxide, glycerin, m-cresol, imidazole, protamine, zinc andsalts thereof (e.g., zinc sulfate), thimerosal, methylparaben,propylparaben, carboxymethylcellulose, chlorobutanol, or heparin. Thestatin may include an excipient.

The term “lyophilized” or “freeze-dried” includes a state of a substancethat has been subjected to a drying procedure such as lyophilization,where at least 50% of moisture has been removed. The medical deviceand/or statin may be lyophilized or freeze-dried.

A “preservative” includes a bacteriostatic, bacteriocidal, fungistaticor fungicidal compound that is generally added to formulations to retardor eliminate growth of bacteria or other contaminating microorganisms inthe formulations. Preservatives include, for example, benzyl alcohol,phenol, benzalkonium chloride, m-cresol, thimerosol, chlorobutanol,methylparaben, propylparaben and the like. Other examples ofpharmaceutically acceptable preservatives can be found in the USP. Thestatin and/or medical device may have preservatives or be preservativefree.

In some embodiments, the medical device (e.g., drug depot) has poresthat allow release of the drug from the depot. The drug depot will allowfluid in the depot to displace the drug. However, cell infiltration intothe depot will be prevented by the size of the pores of the depot. Inthis way, in some embodiments, the depot should not function as a tissuescaffold and allow tissue growth. Rather, the drug depot will solely beutilized for drug delivery. In some embodiments, the pores in the drugdepot will be less than 250 to 500 microns. This pore size will preventcells from infiltrating the drug depot and laying down scaffoldingcells. Thus, in this embodiment, drug will elute from the drug depot asfluid enters the drug depot, but cells will be prevented from entering.Pores can be made using, for example a pore forming agent includingpolyhydroxy compounds such as a carbohydrate, a polyhydroxy aldehyde, apolyhydroxy ketone, a glycogen, an aldose, a sugar, a mono- orpolysaccharide, an oligosaccharide, a polyhydroxy carboxylic compound,polyhydroxy ester compound, a cyclodextrin, a polyethylene glycolpolymer, a glycerol an alginate, a chitosan, a polypropylene glycolpolymer, a polyoxyethylene-polyoxypropylene block co-polymer, agar, orhyaluronic acid or polyhydroxy derivative compounds, hydroxypropylcellulose, tween, sorbitan, sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitanmonooleate, or a combination thereof. In some embodiments, where thereare little or no pores, the drug will elute out from the drug depot bythe action of enzymes, by hydrolytic action and/or by other similarmechanisms in the human body.

In some embodiments, the medical device may comprise DLG. Theabbreviation “DLG” refers to poly(DL-lactide-co-glycolide). In someembodiments, the medical device may comprise DL. The abbreviation “DL”refers to poly(DL-lactide). In some embodiments, the medical device maycomprise LG. The abbreviation “LG” refers topoly(L-lactide-co-glycolide). In some embodiments, the medical devicemay comprise CL. The abbreviation “CL” refers to polycaprolactone. Insome embodiments, the medical device may comprise DLCL. The abbreviation“DLCL” refers to poly(DL-lactide-co-caprolactone). In some embodiments,the medical device may comprise LCL. The abbreviation “LCL” refers topoly(L-lactide-co-caprolactone). In some embodiments, the medical devicemay comprise G. The abbreviation “G” refers to polyglycolide. In someembodiments, the medical device may comprise PEG. The abbreviation “PEG”refers to poly(ethylene glycol). In some embodiments, the medical devicemay comprise PLGA. The abbreviation “PLGA” refers topoly(lactide-co-glycolide) also known as poly(lactic-co-glycolic acid),which are used interchangeably. In some embodiments, the medical devicemay comprise PLA. The abbreviation “PLA” refers to polylactide. In someembodiments, the medical device may comprise POE. The abbreviation “POE”refers to poly(orthoester).

Reference will now be made in detail to certain embodiments of theinvention. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

In some embodiments, implantable medical devices and methods areprovided that retain the statin at, near or in the bone defect (e.g.,fracture, void, etc.) to facilitate healing of the bone defect and avoidadverse local tissue reactions to the statin. In some embodiments, theimplantable medical devices provided are osteoconductive and allow gapsand fractures to be filled with new bridging bone faster. All of whichleads to a reduced time for healing. In some embodiments, theimplantable medical devices and methods provided are easy and lesscostly to manufacture because the active ingredient is a small moleculestatin, as opposed to a larger, and, sometimes, more expensive and lessstable growth factor.

In one embodiment, the implantable medical devices and methods alloweasy delivery to the bone defect (e.g., fracture site, synovial joint,at or near the spinal column, etc.) using a gel that hardens uponcontact with the target tissue. In this way, accurate and preciseimplantation of the medical device in a minimally invasive procedure canbe accomplished. The headings below are not meant to limit thedisclosure in any way; embodiments under any one heading may be used inconjunction with embodiments under any other heading.

Medical Device

In some embodiments, the medical device can be a matrix that provides atissue scaffold for the cells to guide the process of tissue formationin vivo in three dimensions. The morphology of the matrix guides cellmigration and cells are able to migrate into or over the matrix. Thecells then are able to proliferate and synthesize new tissue and formbone and/or cartilage. In some embodiments, one or more tissue matricesare stacked on one another.

The matrix is porous and configured to allow influx of at least boneand/or cartilage cells therein. By porous is meant that the matrix has aplurality of pores. The pores of the matrix are a size large enough toallow influx of blood, other bodily fluid, and progenitor and/or boneand/or cartilage cells into the interior to guide the process of tissueformation in vivo in three dimensions.

In some embodiments, the matrix comprises a plurality of pores. In someembodiments, at least 10% of the pores are between about 50 micrometersand about 500 micrometers at their widest points. In some embodiments,at least 20% of the pores are between about 50 micrometers and about 250micrometers at their widest points. In some embodiments, at least 30% ofthe pores are between about 50 micrometers and about 150 micrometers attheir widest points. In some embodiments, at least 50% of the pores arebetween about 10 micrometers and about 500 micrometers at their widestpoints. In some embodiments, at least 90% of the pores are between about50 micrometers and about 250 micrometers at their widest points. In someembodiments, at least 95% of the pores are between about 50 micrometersand about 150 micrometers at their widest points. In some embodiments,100% of the pores are between about 10 micrometers and about 500micrometers at their widest points.

In some embodiments, the matrix has a porosity of at least about 30%, atleast about 50%, at least about 60%, at least about 70%, at least about90% or at least about 95%, or at least about 99%. The pores may supportingrowth of cells, formation or remodeling of bone, cartilage and/orvascular tissue.

The matrix is also configured to retain a statin that has anabolicactivity and stimulates bone morphogenic protein expression and bonegrowth into the matrix to heal bone. In some embodiments, the matrixallows for sustained release of the statin over 2 weeks to 6 months orabout 2 weeks to 4 weeks.

In some embodiments, the matrix does not contain any growth factor. Insome embodiments, the matrix does contain one or more growth factors.

In some embodiments, the porous interior can hold the statin within thematrix and because the interior is porous, the statin is evenlydistributed throughout the matrix when the statin is injected, soaked,contacted, or lyophilized into the matrix.

In some embodiments, a statin will be held within the interior of thematrix and released into the environment surrounding the matrix (e.g.,bone defect, osteochondral defect, etc.) as the matrix degrades overtime.

In some embodiments, the matrix or drug depot comprises biodegradablepolymeric and non-polymeric material. For example, the matrix maycomprises one or more poly (alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), poly(L-lactide),polyglycolide (PG), polyglycolic acid (PGA), polyethylene glycol (PEG)conjugates of poly (alpha-hydroxy acids), polyorthoesters (POE),polyaspirins, polyphosphagenes, collagen, hydrolyzed collagen, gelatin,hydrolyzed gelatin, fractions of hydrolyzed gelatin, elastin, starch,pre-gelatinized starch, hyaluronic acid, chitosan, alginate, albumin,fibrin, vitamin E analogs, such as alpha tocopheryl acetate, d-alphatocopheryl succinate, D,L-lactide, or L-lactide, -caprolactone,dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, POE, SAIB (sucrose acetateisobutyrate), polydioxanone, methylmethacrylate (MMA), MMA andN-vinylpyyrolidone, polyamide, oxycellulose, copolymer of glycolic acidand trimethylene carbonate, polyesteramides, polyetheretherketone,polymethylmethacrylate, silicone, hyaluronic acid, tyrosinepolycarbonate, chitosan, or combinations thereof.

In some embodiments, the matrix (e.g., exterior and/or interior)comprises collagen. Exemplary collagens include human or non-human(bovine, ovine, and/or porcine), as well as recombinant collagen orcombinations thereof. Examples of suitable collagen include, but are notlimited to, human collagen type I, human collagen type II, humancollagen type III, human collagen type IV, human collagen type V, humancollagen type VI, human collagen type VII, human collagen type VIII,human collagen type IX, human collagen type X, human collagen type XI,human collagen type XII, human collagen type XIII, human collagen typeXIV, human collagen type XV, human collagen type XVI, human collagentype XVII, human collagen type XVIII, human collagen type XIX, humancollagen type XXI, human collagen type XXII, human collagen type XXIII,human collagen type XXIV, human collagen type XXV, human collagen typeXXVI, human collagen type XXVII, and human collagen type XXVIII, orcombinations thereof. Collagen further may comprise hetero- andhomo-trimers of any of the above-recited collagen types. In someembodiments, the collagen comprises hetero- or homo-trimers of humancollagen type I, human collagen type II, human collagen type III, orcombinations thereof.

In some embodiments, the matrix comprises collagen-containingbiomaterials from the implant market which, when placed in a bonedefect, provide scaffolding around which the patient's new bone and/orcartilage will grow, gradually replacing the carrier matrix as thetarget site heals. Examples of suitable carrier matrices may include,but are not limited to, the MasterGraft® Matrix produced by MedtronicSofamor Danek, Inc., Memphis, Tenn.; MasterGraft® Putty produced byMedtronic Sofamor Danek, Inc., Memphis, Tenn.; Absorbable CollagenSponge (“ACS”) produced by Integra LifeSciences Corporation, Plainsboro,N.J.; bovine skin collagen fibers coated with hydroxyapatite, e.g.Healos®. marketed by Johnson & Johnson, USA; collagen sponges, e.g.Hemostagene® marketed by Coletica S A, France, or e.g. Helisat® marketedby Integra Life Sciences Inc., USA; Collagraft® Bone Graft Matrixproduced by Zimmer Holdings, Inc., Warsaw, Ind., Osteofil® (MedtronicSofamor Danek, Inc., Memphis, Tenn.), Allomatrix® (Wright), Grafton®(Osteotech), DBX® (MTF/Synthes), Bioset® (Regeneration Technologies),matrices consisting of mineral phases such as Vitoss® (Orthivista),Osteoset® (Wright) or mixed matrices such as CopiOs® (Zimmer), orSunnmax Collagen Bone Graft Matrix (Sunmax).

In one embodiment, the matrix can be packaged as a product including acontainer body holding an unhydrated matrix to be hydrated, and aremovable seal operable to prevent passage of moisture into contact withthe medical material. Exemplary materials to be hydrated includeMasterGraft® Matrix and a MasterGraft® Putty. Exemplary hydrating fluidsinclude blood, bone marrow, saline, water, or other fluid. The hydratingfluid may contain the statin and be used to soak the statin in thematrix.

For example, the statin can be applied to MasterGraft® Matrix orMasterGraft® Putty, which comprises type I bovine collagen and a calciumphosphate mineral phase composed of 15% hydroxyapatite and 85%beta-tricalcium phosphate. The matrix can be hydrated just prior to useso that, in some embodiments, it becomes a flowable material. Such amaterial can be injected through a cannula or other conduit into an invivo location.

In some embodiments, the matrix is compression resistant where thematrix resists reduction in size or an increase in density when a forceis applied as compared to matrices that are not compression resistant.In various embodiments, the matrix resists compression by at least 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, or more in one or all directions when a force is appliedto the matrix.

Gel

In various embodiments, the statin is administered in a gel. The gel mayhave a pre-dosed viscosity in the range of about 1 to about 2000centipoise (cps), 1 to about 200 cps, or 1 to about 100 cps. After thegel is administered to the target site, the viscosity of the gel willincrease and the gel will have a modulus of elasticity (Young's modulus)in the range of about 1×10² to about 6×10⁵ dynes/cm², or 2×10⁴ to about5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In one embodiment, a depot comprises an adherent gel comprising statinthat is evenly distributed throughout the gel. The gel may be of anysuitable type, as previously indicated, and should be sufficientlyviscous so as to prevent the gel from migrating from the targeteddelivery site once deployed; the gel should, in effect, “stick” oradhere to the targeted tissue site. The gel may, for example, solidifyupon contact with the targeted tissue or after deployment from atargeted delivery system. The targeted delivery system may be, forexample, a syringe, a catheter, needle or cannula or any other suitabledevice. The targeted delivery system may inject the gel into or on thetargeted tissue site. The therapeutic agent may be mixed into the gelprior to the gel being deployed at the targeted tissue site. In variousembodiments, the gel may be part of a two-component delivery system andwhen the two components are mixed, a chemical process is activated toform the gel and cause it to stick or to adhere to the target tissue.

In various embodiments, a gel is provided that hardens or stiffens afterdelivery. Typically, hardening gel formulations may have a pre-dosedmodulus of elasticity in the range of about 1×10² to about 3×10⁵dynes/cm², or 2×10⁴ to about 2×10⁵ dynes/cm², or 5×10⁴ to about 1×10⁵dynes/cm². The post-dosed hardening gels (after delivery) may have arubbery consistency and have a modulus of elasticity in the range ofabout 1×10² to about 2×10⁶ dynes/cm², or 1×10⁵ to about 7×10⁵ dynes/cm²,or 2×10⁵ to about 5×10⁵ dynes/cm².

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances. In some embodiments, the polymer comprises 20 wt. % to90 wt. % of the formulation.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The choice of method to vary molecularweight is typically determined by the composition of the gel (e.g.,polymer, versus non-polymer). For example in various embodiments, whenthe gel comprises one or more polymers, the degree of polymerization canbe controlled by varying the amount of polymer initiators (e.g. benzoylperoxide), organic solvents or activator (e.g. DMPT), crosslinkingagents, polymerization agent, incorporation of chain transfer or chaincapping agents and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel that includes a high molecular weight polymer tends tocoagulate or solidify more quickly than a polymeric composition thatincludes a low-molecular weight polymer. Polymeric gel formulations thatinclude high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel that includes low-molecularweight polymers. In various embodiments, the molecular weight of thepolymer can be a wide range of values. The average molecular weight ofthe polymer can be from about 1000 to about 10,000,000; or about 1,000to about 1,000,000; or about 5,000 to about 500,000; or about 10,000 toabout 100,000; or about 20,000 to 50,000 g/mol.

When the gel is designed to be a flowable gel, it can vary from lowviscosity, similar to that of water, to high viscosity, similar to thatof a paste, depending on the molecular weight and concentration of thepolymer used in the gel. The viscosity of the gel can be varied suchthat the polymeric composition can be applied to a patient's tissues byany convenient technique, for example, by brushing, dripping, injecting,or painting. Different viscosities of the gel will depend on thetechnique used to apply the composition.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and may have a longerdegradation time). Typically, when the polymers have similar componentsbut different MWs, a gel with a high molecular weight provides astronger matrix and the matrix takes more time to degrade. In contrast,a gel with a low molecular weight degrades more quickly and provides asofter matrix. In various embodiments, the polymer of the depot or thedepot has a molecular weight, as shown by the inherent viscosity, fromabout 0.10 dL/g to about 1.2 dL/g or from about 0.10 dL/g to about 0.40dL/g. Other IV ranges include but are not limited to about 0.05 to about0.15 dL/g, about 0.10 to about 0.20 dL/g, about 0.15 to about 0.25 dL/g,about 0.20 to about 0.30 dL/g, about 0.25 to about 0.35 dL/g, about 0.30to about 0.35 dL/g, about 0.35 to about 0.45 dL/g, about 0.40 to about0.45 dL/g, about 0.45 to about 0.50 dL/g, about 0.50 to about 0.70 dL/g,about 0.60 to about 0.80 dL/g, about 0.70 to about 0.90 dL/g, and about0.80 to about 1.00 dL/g.

In some embodiments, if the polymer materials have different chemistries(e.g., high MW DLG 5050 and low MW DL), the high MW polymer may degradefaster than the low MW polymer. In various embodiments, the gel can havea viscosity of about 300 to about 5,000 centipoise (cp). In otherembodiments, the gel can have a viscosity of from about 5 to about 300cps, from about 10 cps to about 50 cps, or from about 15 cps to about 75cps at room temperature. The gel may optionally have a viscosityenhancing agent such as, for example, hydroxypropyl cellulose,hydroxypropyl methylcellulose, hydroxyethyl methylcellulose,carboxymethylcellulose and salts thereof, Carbopol,poly-(hydroxyethylmethacrylate), poly-(methoxyethylmethacrylate),poly(methoxyethoxyethyl methacrylate), polymethylmethacrylate (PMMA),methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol,mPEG, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG900, PEG 1000, PEG 1450, PEG 3350, PEG 4500, PEG 8000 or combinationsthereof.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. A desirable property for the hydrogel to have is the ability torespond rapidly to mechanical stresses, particularly shears and loads,in the human body.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid and poly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol (e.g.,PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with statin. In one embodiment, themicrospheres provide for a sustained release of the statin. In yetanother embodiment, the gel, which is biodegradable, prevents themicrospheres from releasing the statin; the microspheres thus do notrelease the statin until they have been released from the gel. Forexample, a gel may be deployed around a target tissue site (e.g., anerve root). Dispersed within the gel may be a plurality of microspheresthat encapsulate the desired therapeutic agent. Certain of thesemicrospheres degrade once released from the gel, thus releasing thestatin.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse thestatin. In some situations, this may be desirable; in others, it may bemore desirable to keep the statin tightly constrained to a well-definedtarget site. The present invention also contemplates the use of adherentgels to so constrain dispersal of the therapeutic agent. These gels maybe deployed, for example, at or near the wound, in a disc space, in aspinal canal, or in surrounding tissue.

In some embodiments, the statin can be dispersed in a gel and can beapplied accurately to the bone defect, providing a continuous,uninterrupted covering over the defect. The entire defect is therebysubjected to the improved healing environment created by the gel, andthe bound can heal evenly and consistently throughout. Gels can be madeto stay where applied, providing prolonged control of the healingenvironment.

In some embodiments, the statin can be applied to the bone defect in agel form. The statin can be loaded in the gel in an amount of from about1 wt % to about 25 wt %, or about 5 wt. % to about 10 wt. %. In someembodiments, the amount can be from about 10 wt. % to about 20 wt. %. Insome embodiment there is a higher loading of statin, e.g., at least 20wt. %, at least 30 wt. %, at least 40 wt. %, at least 50 wt. %, at least60 wt. %, at least 70 wt. %, at least 80 wt. %, or at least 90 wt. %.

FIG. 1 illustrates a front view of a joint capsule showing percutaneousinjections of the medical device (a gel containing a statin) into oraround a hematoma at an early stage of fracture healing in long bones.In this embodiment, the gel is a hardening gel and applied via cannulato the hematoma near the fracture site bilaterally. The gel having apolymer will degrade and release the statin and be delivered to thefracture site by the vasculature. The statin will cause increase in bonemorphogenic protein and an increase of at least progenitor, and/or bonecells at, near or in the bone defect so that healing of the fracturesite will be enhanced.

One exemplary embodiment comprises a drug depot (e.g., gel) containingthe statin that releases the statin from the drug depot for a period of2 to 4 weeks before it entirely degrades and the drug depot releasesabout 0.1 mg/day to about 4 mg/day of the statin. For example, the drugdepot can release about 2 mg of the statin over about a 2 week period orabout 100 mg of the statin over about a 4 week period. The volume of thedrug depot can be from about 1 ml to about 5 ml and be deliveredpercutaneously locally at, near or in the fracture (e.g., long-bonefracture with or without intramedullary nail, femur fracture, ulna ortibia osteotomy, bone void, etc.) to enhance bone growth and healing. Insome embodiments, the depot can be premixed by the practitioner fordelivery. In some embodiments, the depot can be formulated by themanufacturer in a ready to use package for delivery (e.g.,prefilled-syringe, or pre-packaged depot, etc.).

In some embodiments, the statin can be in the range of about 0.01 to 10,more usually 0.025 to 5 or 0.05 to 2.5 mg/kg/day, where the amount maybe modified to some degree when treating a human host. Generally, theamount of statin delivered to the mammal can be in the range of about0.1 to 5, usually 0.1 to 2 mg/kg/day, with modifications as appropriatein accordance with the particular mode of treatment and the indication.In some embodiments, the dosage range will be about 5 to 250micrograms/day. Desirably during the course of treatment, the bloodconcentration of the statin can be, for example, in the range of about0.5 to 5, more usually 1 to 5 ng/ml. In some embodiments, the treatmentduration for humans will generally be greater than 1 day, usuallygreater than 2 days, more usually greater than about 5 days, desirablyup to and including 10 days and not more than about 65 days, usually notmore than about 25 days, and more usually not more than about 15 days,generally not more than 10 days. Treatment is terminated when furthertreatment results in no tissue enhancement or deleterious effects, suchas side effects of the drug and diminished positive or negativeosteogenic response to the drug.

In some embodiments, the present application includes an implantableosteoconductive matrix that is in the form of a medical putty, andincludes methods and materials that are useful for preparing such anosteoconductive medical putty. Preferred medical putties possess acombination of advantageous properties including a mineral content,malleability, cohesiveness, and shape retention. For example, when thematrix is implanted into a target tissue site (e.g., bone defect, void,fracture, etc.), the matrix will stay together at the target tissuesite. In the context of putties containing insoluble collagen fibers,upon stretching, the advantageous putties exhibit elongation, duringwhich the existence of substantial levels of intermeshed collagen fibersclinging to one another becomes apparent.

As used herein, the term “shape-retaining” includes that the matrix(e.g., putty, flowable material, paste, etc.) is highly viscous andunless acted upon with pressure tends to remain in the shape in which itis placed. The pressure can be by hand, machine, or from the deliverydevice (injection from a syringe). In some embodiments, the shaperetaining feature of the matrix can be contrasted to thinner liquidmatrices or liquid paste forms, which readily flow, and thus would poolor puddle upon application to a surface.

In certain features of the current application, novel combination ofingredients provide a medical putty material that not only contains asignificant, high level of large particulate mineral particles, but alsoexhibits superior properties with respect to malleability, cohesiveness,and shape retention.

In some embodiments, the matrix of the present application will includea combination of soluble collagen and insoluble collagen. In someembodiments, the matrix does not include any soluble collagen. “Solublecollagen” refers to the solubility of individual tropocollagen moleculesin acidic aqueous environments. Tropocollagen may be considered themonomeric unit of collagen fibers and its triple helix structure is wellrecognized. “Insoluble collagen” as used herein refers to collagen thatcannot be dissolved in an aqueous alkaline or in any inorganic saltsolution without chemical modification, and includes for example hides,splits and other mammalian or reptilian coverings. For example, “naturalinsoluble collagen” can be derived from the corium, which is theintermediate layer of an animal hide (e.g. bovine, porcine, etc.) thatis situated between the grain and the flesh sides. “Reconstitutedcollagen” is essentially collagen fiber segments that have beendepolymerized into individual triple helical molecules, then exposed tosolution and then reassembled into fibril-like forms.

The matrix that is in the form of a putty contains insoluble collagenfibers. In some embodiments, the matrix comprises no soluble collagenfibers. In some embodiments, the matrix comprises both soluble andinsoluble collagen fibers.

The soluble collagen and insoluble collagen fibers can first be preparedseparately, and then combined. Both the soluble collagen and theinsoluble collagen fibers can be derived from bovine hides, but can alsobe prepared from other collagen sources (e.g. bovine tendon, porcinetissues, recombinant DNA techniques, fermentation, etc.).

In certain embodiments, the putty comprises insoluble collagen fibers ata level of 0.04 g/cc to 0.1 g/cc of the putty, and soluble collagen at alevel of 0.01 g/cc to 0.08 g/cc of the putty. In other embodiments, theputty includes insoluble collagen fibers at a level of about 0.05 to0.08 g/cc in the putty, and soluble collagen at a level of about 0.02 toabout 0.05 g/cc in the putty. In general, putties may include insolublecollagen fibers in an amount (percent by weight) that is at least equalto or greater than the amount of soluble collagen, to contributebeneficially to the desired handling and implant properties of the puttymaterial. In advantageous embodiments, when the putty contains collagen,the insoluble collagen fibers and soluble collagen can be present in aweight ratio of 4:1 to 1:1, more advantageously about 75:25 to about60:40. Further still, additional desired putties include the insolublecollagen fibers and soluble collagen in a weight ratio of about 75:25 toabout 65:35, and in one specific embodiment about 70:30. The insolublecollagen fibers, in some embodiments, will be in the composition morethan the soluble collagen fibers.

In some embodiments, the implantable osteoconductive matrix is a puttycomprising ceramic and collagen and the ceramic has a density of about0.15 g/cc to about 0.45 g/cc and the collagen has a density of about0.02 g/cc to about 1.0 g/cc of the putty and the putty comprises fromabout 60% to about 90% by volume of a liquid or about 60% to about 90%liquid volume percentage.

In some embodiments, the implantable osteoconductive matrix is a puttycomprising ceramic and collagen and the ceramic has a density of about0.10 g/cc and the collagen has a density of about 0.02 g/cc of the puttybefore the putty is hydrated with a liquid. Thus, in this embodiment,the putty is in its dry weight form.

In some embodiments, the implantable osteoconductive matrix is a puttycomprising ceramic and collagen and the ceramic has a density of about0.29 g/cc and the collagen has a density of about 0.06 g/cc of the puttyand the putty comprises a liquid that occupies from about 80% to about85% by volume of the final volume of the putty after the putty ishydrated with a liquid.

One suitable putty for use in the present application is MasterGraft®Putty produced by Medtronic Sofamor Danek, Inc.

Medical putties of the present application also include an amount of aparticulate mineral material. In certain embodiments, the particulatemineral is incorporated in the putty at a level of at least about 0.25g/cc of putty, typically in the range of about 0.25 g/cc to about 0.35g/cc. Such relatively high levels of mineral will be helpful inproviding a scaffold for the ingrowth of new bone.

In some embodiment, the putty comprises a natural or synthetic mineralthat is effective to provide a scaffold for bone ingrowth.Illustratively, the mineral may be selected from one or more materialsfrom the group consisting of bone particles, Bioglass, tricalciumphosphate, biphasic calcium phosphate, hydroxyapatite, corralinehydroxyapatite, and biocompatible ceramics. Biphasic calcium phosphateis a particularly desirable synthetic ceramic for use in the presentapplication. Such biphasic calcium phosphate can have a tricalciumphosphate:hydroxyapatite weight ratio of about 50:50 to about 95:5, morepreferably about 70:30 to about 95:5, even more preferably about 80:20to about 90:10, and most preferably about 85:15. The mineral materialcan be particulate having an average particle diameter between about 0.4and 5.0 mm, more typically between about 0.4 and 3.0 mm, and desirablybetween about 0.4 and 2.0 mm.

A putty of the present application can include a significant proportionof a liquid carrier, which will generally be an aqueous liquid such aswater, saline, dextrose, buffered solutions or the like. In one aspect,a malleable, cohesive, shape-retaining putty of the present applicationcomprises about 60% to 75% by weight of an aqueous liquid medium, suchas water, advantageously about 65% to 75% by weight of an aqueous liquidmedium (e.g. water) and a statin.

A putty of the present application includes a statin wherein the statinis in the putty from 0.1 mg/cc to 100 mg/cc. In some embodiments, theputty releases 40 ng to about 5 mg of the statin every hour.

In some embodiments, the matrix releases at stating at a dose of about 1mg to about 100 mg/day (e.g., 1.6 mg to 3.2 mg/day) for up to 28 daysfor bone growth. In some embodiments, the load of statin in the matrixis from about 20 mg to 500 mg, for example 90 mg to 450 mg.

In use, the putty implant compositions are implanted at a site at whichbone growth is desired, e.g. to treat a disease, defect or location oftrauma, and/or to promote artificial arthrodesis. The putty enablestheir positioning, shaping and/or molding within voids, defects or otherareas in which new bone growth is desired. In particularly advantageousembodiments, the shape-retaining property of the putty will desirablyprovide sufficient three-dimensional integrity to resist substantialcompression when impinged by adjacent soft tissues of the body at a bonyimplant site.

Once in place, the osteoconductive putty can effectively induce andsupport the ingrowth of bone into the desired area even in a primatesubject such as a human exhibiting a relatively slow rate of boneformation.

Osteoconductive putty compositions are especially advantageous when usedin bones or bone portions that are vascularized to only moderate or lowlevels. These areas present particularly low rates of bone formation,and as such the rapid resorption of the carrier possess enhanceddifficulties. Examples of moderate or only slightly vascularized sitesinclude, for example, transverse processes or other posterior elementsof the spine, the diaphysis of long bones, in particular the middiaphysis of the tibia, and cranial defects.

In addition, in accordance with other aspects of the presentapplication, the putty compositions can be incorporated in, on or arounda load-bearing spinal implant device (e.g. having a compressive strengthof at least about 10000 N) such as a fusion cage, dowel, or other devicehaving a pocket, chamber or other cavity for containing anosteoconductive matrix, and used in a spinal fusion such as an interbodyfusion.

Mineral Particles

In some embodiments, the matrix may comprise mineral particles thatoffers compression resistance. In some embodiments, the particlescomprise at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95% by weight of the matrix. In someembodiments, the particles are predominantly any shape (e.g., round,spherical, elongated (powders, chips, fibers, cylinders, etc.).

In some embodiments, the porosity of the particles comprises from 0 to50%, in some embodiments, the porosity of the particles comprises 5% to25%. In some embodiments, the particles are not entangled with eachother but contact each other and portions of each particle overlap inthe matrix to provide compression resistance. In some embodiments, atleast 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more of theparticles overlap each other in the matrix.

In some embodiments, the particles are randomly distributed throughoutthe matrix. In other embodiments, the particles are uniformly or evenlydistributed throughout the matrix. In some embodiments, the particlesmay be dispersed in the matrix using a dispersing agent. In otherembodiments, the particles may be stirred in the polymer and themechanical agitation will distribute the particles in the matrix untilthe desired distribution is reached (e.g., random or uniform).

In some embodiments, the matrix may comprise a resorbable ceramic (e.g.,hydroxyapatite, tricalcium phosphate, bioglasses, calcium sulfate, etc.)tyrosine-derived polycarbonate poly (DTE-co-DT carbonate), in which thependant group via the tyrosine—an amino acid—is either an ethyl ester(DTE) or free carboxylate (DT) or combinations thereof.

In some embodiments, the matrix may be seeded with harvested bone cellsand/or bone tissue, such as for example, cortical bone, autogenous bone,allogenic bones and/or xenogenic bone. In some embodiments, the matrixmay be seeded with harvested cartilage cells and/or cartilage tissue(e.g., autogenous, allogenic, and/or xenogenic cartilage tissue). Forexample, before insertion into the target tissue site, the matrix can bewetted with the graft bone tissue/cells, usually with bone tissue/cellsaspirated from the patient, at a ratio of about 3:1, 2:1, 1:1, 1:3 or1:2 by volume. The bone tissue/cells are permitted to soak into thematrix provided, and the matrix may be kneaded by hand or machine,thereby obtaining a pliable and cohesive consistency that maysubsequently be packed into the bone defect. In some embodiments, thematrix provides a malleable, non-water soluble carrier that permitsaccurate placement and retention at the implantation site. In someembodiments, the harvested bone and/or cartilage cells can be mixed withthe statin and seeded in the interior of the matrix.

In some embodiments, the particles in the matrix comprise a resorbableceramic, bone, synthetic degradable polymer, hyaluronic acid, chitosanor combinations thereof. In some embodiments, the particles comprisecortical, cancellous, and/or corticocancellous, allogenic, xenogenic ortransgenic bone tissue. The bone component can be fully mineralized orpartially or fully demineralized or combinations thereof. The bonecomponent can consist of fully mineralized or partially or fullydemineralized bone.

In some embodiments, the matrix may contain an inorganic material, suchas an inorganic ceramic and/or bone substitute material. Exemplaryinorganic materials or bone substitute materials include but are notlimited to aragonite, dahlite, calcite, amorphous calcium carbonate,vaterite, weddellite, whewellite, struvite, urate, ferrihydrate,francolite, monohydrocalcite, magnetite, goethite, dentin, calciumcarbonate, calcium sulfate, calcium phosphosilicate, sodium phosphate,calcium aluminate, calcium phosphate, hydroxyapatite, alpha-tricalciumphosphate, dicalcium phosphate, β-tricalcium phosphate, tetracalciumphosphate, amorphous calcium phosphate, octacalcium phosphate, BIOGLASS™fluoroapatite, chlorapatite, magnesium-substituted tricalcium phosphate,carbonate hydroxyapatite, substituted forms of hydroxyapatite (e.g.,hydroxyapatite derived from bone may be substituted with other ions suchas fluoride, chloride, magnesium sodium, potassium, etc.), orcombinations or derivatives thereof.

In some embodiments, by including inorganic ceramics, such as forexample, calcium phosphate, in the matrix, this will act as a localsource of calcium and phosphate to the cells attempting to deposit newbone. The inorganic ceramic also provides compression resistance andload bearing characteristics to the matrix.

In some embodiments, the mineral particles in the matrix comprisetricalcium phosphate and hydroxyapatite in a ratio of about 80:20 toabout 90:10. In some embodiments, the mineral particles in the matrixcomprise tricalcium phosphate and hydroxyapatite in a ratio of about85:15.

In some embodiments, the matrix has a density of between about 1.6g/cm³, and about 0.05 g/cm³. In some embodiments, the matrix has adensity of between about 1.1 g/cm³, and about 0.07 g/cm³. For example,the density may be less than about 1 g/cm³, less than about 0.7 g/cm³,less than about 0.6 g/cm³, less than about 0.5 g/cm³, less than about0.4 g/cm³, less than about 0.3 g/cm³, less than about 0.2 g/cm³, or lessthan about 0.1 g/cm³.

In some embodiments, the diameter or diagonal of the matrix can rangefrom 1 mm to 50 mm. In some embodiments, the diameter or diagonal of thematrix can range from 1 mm to 30 mm, or 5 mm to 10 mm which is smallenough to fit through an endoscopic cannula, but large enough tominimize the number of matrices needed to fill a large the bone defect(e.g., osteochondral defect). In some embodiments, at the time ofsurgery, the matrix can be soaked with a statin and molded by thesurgeon to the desired shape to fit the tissue or bone defect.

It will be appreciated by those with skill in the art that the matrixcan be administered to the target site using a cannula or needle thatcan be a part of a drug delivery device e.g., a syringe, a gun drugdelivery device, or any medical device suitable for the application of adrug to a targeted organ or anatomic region. The cannula or needle ofthe matrix device is designed to cause minimal physical andpsychological trauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space, for example, alongan inflammed nerve root and the drug depot implanted at this site fortreating the condition. Typically, the transforaminal approach involvesapproaching the intervertebral space through the intervertebralforamina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes, but is not limited to, from about0.05 to about 1.655. The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 22 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the matrix, the cannula or needle includesdose radiographic markers that indicate location at or near the sitebeneath the skin, so that the user may accurately position the depot ator near the site using any of the numerous diagnostic imagingprocedures. Such diagnostic imaging procedures include, for example,X-ray imaging or fluoroscopy. Examples of such radiographic markers

Method of Making the Matrix

In some embodiments, the matrix may be made by injection molding,compression molding, blow molding, thermoforming, die pressing, slipcasting, electrochemical machining, laser cutting, water-jet machining,electrophoretic deposition, powder injection molding, sand casting,shell mold casting, lost tissue scaffold casting, plaster-mold casting,ceramic-mold casting, investment casting, vacuum casting, permanent-moldcasting, slush casting, pressure casting, die casting, centrifugalcasting, squeeze casting, rolling, forging, swaging, extrusion,shearing, spinning, powder metallurgy compaction or combinationsthereof.

One form of manufacturing the matrix involves casting the matrixmaterial in a mold. The matrix material can take on the shape of themold such as, crescent, quadrilateral, rectangular, cylindrical, plug,or any other shape. Additionally, the surface of the mold may be smoothor may include raised features or indentations to impart features to thematrix. Features from the mold can be imparted to the matrix as thematrix material in the mold is dried. In particular aspects, a roughenedor friction engaging surface can be formed on the superior surfaceand/or the inferior surface of the matrix body. In some embodiments,protuberances or raised portions can be imparted on the superior surfaceand/or the inferior surface from the mold. Such examples ofprotuberances or raised portions are ridges, serrations, pyramids, andteeth, or the like.

In some embodiments, in manufacturing the matrix, a mixture of thematrix material (e.g., collagen) is combined with the mineral particlesand a liquid to wet the material and form a slurry. Any suitable liquidcan be used including, for example, aqueous preparations such as water,saline solution (e.g. physiological saline), sugar solutions, proticorganic solvents, or liquid polyhydroxy compounds such as glycerol andglycerol esters, or mixtures thereof. The liquid may, for example,constitute about 5 to about 70 weight percent of the mixed compositionprior to the molding operation. Certain liquids such as water can beremoved in part or essentially completely from the formed matrix usingconventional drying techniques such as air drying, heated drying,lyophilization, or the like.

In one embodiment of manufacture, a collagen mixture can be combinedwith mineral particles and a liquid, containing a statin and desirablywith an aqueous preparation, to form a slurry. Excess liquid can beremoved from the slurry by any suitable means, including for example byapplying the slurry to a liquid-permeable mold or form and draining awayexcess liquid.

Before, during or after molding, including in some instances theapplication of compressive force to the collagen containing material,the collagen material can be subjected to one or more additionaloperations such as heating, lyophilizing and/or crosslinking to make theporous collagen interior or exterior of the matrix the desired porosityand to disperse the statin within the matrix. In this regard,crosslinking can be used to improve the strength of the formed matrix.Alternatively, one or more of the surfaces of the matrix can becrosslinked to reduce the size of the pores of the porous interior andthereby form the exterior of the matrix that is less permeable and/orless porous than the porous interior. Crosslinking can be achieved, forexample, by chemical reaction, the application of energy such as radiantenergy (e.g. UV light or microwave energy), drying and/or heating anddye-mediated photo-oxidation; dehydrothermal treatment; enzymatictreatment or others.

Chemical crosslinking agents will generally be preferred, includingthose that contain bifunctional or multifunctional reactive groups, andwhich react with matrix. Chemical crosslinking can be introduced byexposing the matrix material to a chemical crosslinking agent, either bycontacting it with a solution of the chemical crosslinking agent or byexposure to the vapors of the chemical crosslinking agent. Thiscontacting or exposure can occur before, during or after a moldingoperation. In any event, the resulting material can then be washed toremove substantially all remaining amounts of the chemical crosslinkerif needed or desired for the performance or acceptability of the finalimplantable matrix.

Suitable chemical crosslinking agents include mono- and dialdehydes,including glutaraldehyde and formaldehyde; polyepoxy compounds such asglycerol polyglycidyl ethers, polyethylene glycol diglycidyl ethers andother polyepoxy and diepoxy glycidyl ethers; tanning agents includingpolyvalent metallic oxides such as titanium dioxide, chromium dioxide,aluminum dioxide, zirconium salt, as well as organic tannins and otherphenolic oxides derived from plants; chemicals for esterification orcarboxyl groups followed by reaction with hydrazide to form activatedacyl azide functionalities in the collagen; dicyclohexyl carbodiimideand its derivatives as well as other heterobifunctional crosslinkingagents; hexamethylene diisocyante; and/or sugars, including glucose,will also crosslink the matrix material.

In some embodiments, the matrices are formed by mixing the mineralparticles in with a polymer slurry such as collagen and statin andpouring into a shaped mold. The composite mixture is freeze dried andpossibly chemically crosslinked and cut to the final desired shape andthen the matrix can be re-hydrated before use, where the surgeon canmold it to fit the bone defect.

In some embodiments, the matrix may comprise sterile and/or preservativefree material. The matrix can be implanted by hand or machine inprocedures such as for example, laparoscopic, arthroscopic,neuroendoscopic, endoscopic, rectoscopic procedures or the like.

The matrix of the present application may be used to repair bone and/orcartilage at a target tissue site, e.g., one resulting from injury,defect brought about during the course of surgery, infection, malignancyor developmental malformation. The matrix can be utilized in a widevariety of orthopedic, periodontal, neurosurgical, oral andmaxillofacial surgical procedures such as the repair of simple and/orcompound fractures and/or non-unions; external and/or internalfixations; joint reconstructions such as arthrodesis; generalarthroplasty; cup arthroplasty of the hip; femoral and humeral headreplacement; femoral head surface replacement and/or total jointreplacement; repairs of the vertebral column including spinal fusion andinternal fixation; tumor surgery, e.g., deficit filling; discectomy;laminectomy; excision of spinal cord tumors; anterior cervical andthoracic operations; repairs of spinal injuries; scoliosis, lordosis andkyphosis treatments; intermaxillary fixation of fractures; mentoplasty;temporomandibular joint replacement; alveolar ridge augmentation andreconstruction; inlay implantable matrices; implant placement andrevision; sinus lifts; cosmetic procedures; etc. Specific bones whichcan be repaired or replaced with the implantable matrix herein includethe ethmoid, frontal, nasal, occipital, parietal, temporal, mandible,maxilla, zygomatic, cervical vertebra, thoracic vertebra, lumbarvertebra, sacrum, rib, sternum, clavicle, scapula, humerus, radius,ulna, carpal bones, metacarpal bones, phalanges, ilium, ischium, pubis,femur, tibia, fibula, patella, calcaneus, tarsal and/or metatarsalbones.

Depot

The drug depot contains the statin. The loading of the statin in thedepot (e.g., in percent by weight relative to the weight of the basicstructure) can vary over a wide range, depending on the specificapplication, and can be determined specifically for the particular case.In some embodiments, the statin is in the medical device (e.g., drugdepot) in an amount from about 0.1 wt. % to about 50 wt. %, or about 1wt. % to about 30 wt. %, or about 2.5 wt. % to about 25 wt. %, or about5 wt. % to about 25 wt. %, or about 10 wt. % to about 20 wt. %, or about5 wt. % to about 15 wt. % based on the total weight of the medicaldevice.

In some embodiment there is a higher loading of statin, e.g., at least20 wt. %, at least 30 wt. %, at least 40 wt. %, at least 50 wt. %, atleast 60 wt. %, at least 70 wt. %, at least 80 wt. %, or at least 90 wt.%.

The average molecular weight of the polymer of the depot can be fromabout 1000 to about 10,000,000; or about 1,000 to about 1,000,000; orabout 5,000 to about 500,000; or about 10,000 to about 100,000 or about125,000; or about 20,000 to 50,000 daltons.

In some embodiments, the drug depot has a modulus of elasticity in therange of about 1×10² to about 6×10⁵ dyn/cm², or 2×10⁴ to about 5×10⁵dyn/cm², or 5×10⁴ to about 5×10⁵ dyn/cm². In some embodiments, the drugdepot is in the form of a solid.

In some embodiments, the semi-solid or solid depot may comprise apolymer having a molecular weight, as shown by the inherent viscosity,from about 0.10 dL/g to about 1.2 dL/g or from about 0.10 dL/g to about0.40 dL/g. Other IV ranges include but are not limited to about 0.05 toabout 0.15 dL/g, about 0.10 to about 0.20 dL/g, about 0.15 to about 0.25dL/g, about 0.20 to about 0.30 dL/g, about 0.25 to about 0.35 dL/g,about 0.30 to about 0.35 dL/g, about 0.35 to about 0.45 dL/g, about 0.40to about 0.45 dL/g, about 0.45 to about 0.55 dL/g, about 0.50 to about0.70 dL/g, about 0.55 to about 0.6 dL/g, about 0.60 to about 0.80 dL/g,about 0.70 to about 0.90 dL/g, about 0.80 to about 1.00 dL/g, about 0.90to about 1.10 dL/g, about 1.0 to about 1.2 dL/g, about 1.1 to about 1.3dL/g, about 1.2 to about 1.4 dL/g, about 1.3 to about 1.5 dL/g, about1.4 to about 1.6 dL/g, about 1.5 to about 1.7 dL/g, about 1.6 to about1.8 dL/g, about 1.7 to about 1.9 dL/g, or about 1.8 to about 2.1 dL/g.

The particle size of the statin in the depot can be from about 1 toabout 25 micrometers, or about 5 to 30 or 50 micrometers, however, invarious embodiments ranges from about 1 micron to 250 microns may beused.

In various embodiments, the depot may comprise a bioerodible, abioabsorbable, and/or a biodegradable biopolymer that may provideimmediate release, or sustained release of the statin. Examples ofsuitable sustained release biopolymers include but are not limited topoly (alpha-hydroxy acids), poly (lactide-co-glycolide) (PLGA),polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly (alpha-hydroxy acids), poly(orthoester)s (POE),polyaspirins, polyphosphagenes, collagen, starch, pre-gelatinizedstarch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin,vitamin E analogs, such as alpha tocopheryl acetate, d-alpha tocopherylsuccinate, D,L-lactide, or L-lactide, -caprolactone, dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate)poly(lactide-co-glycolide) (PLGA), polylactide(PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide,D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone,poly(D,L-lactide-co-caprolactone), or poly(L-lactide-co-caprolactone),or copolymers thereof or combinations thereof PEG may be used as aplasticizer for PLGA, but other polymers/excipients may be used toachieve the same effect. PEG imparts malleability to the resultingformulations. In some embodiments, these biopolymers may also be coatedon the drug depot to provide the desired release profile. In someembodiments, the coating thickness may be thin, for example, from about5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 microns to thicker coatings 60,65, 70, 75, 80, 85, 90, 95, 100 microns to delay release of the drugfrom the depot. In some embodiments, the range of the coating on thedrug depot ranges from about 5 microns to about 250 microns or 5 micronsto about 200 microns to delay release from the drug depot.

In various embodiments, the drug depot comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone, poly(lactide-co-glycolide)(PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide,L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone,poly(D,L-lactide-co-caprolactone), or poly(L-lactide-co-caprolactone),or copolymers thereof or a combination thereof.

In some embodiments, the drug depot comprises one or more polymers(e.g., PLA, PLGA, etc.) having a MW of from about 15,000 to about150,000 Da or from about 25,000 to about 100,000 Da.

In some embodiments, the implantable depot compositions having a blendof polymers with different end groups are used the resulting formulationwill have a lower burst index and a regulated duration of delivery. Forexample, one may use polymers with acid (e.g., carboxylic acid) andester end groups (e.g., methyl or ethyl ester end groups). Additionally,by varying the comonomer ratio of the various monomers that form apolymer (e.g., the L/G (lactic acid/glycolic acid) or G/CL (glycolicacid/polycaprolactone) ratio for a given polymer) there will be aresulting depot composition having a regulated burst index and durationof delivery. For example, a depot composition having a polymer with aL/G ratio of 50:50 may have a short duration of delivery ranging fromabout two days to about one month; a depot composition having a polymerwith a L/G ratio of 65:35 may have a duration of delivery of about twomonths; a depot composition having a polymer with a L/G ratio of 75:25or L/CL ratio of 75:25 may have a duration of delivery of about threemonths to about four months; a depot composition having a polymer ratiowith a L/G ratio of 85:15 may have a duration of delivery of about fivemonths; a depot composition having a polymer with a L/CL ratio of 25:75or PLA may have a duration of delivery greater than or equal to sixmonths; a depot composition having a terpolymer of CL/G/L with G greaterthan 50% and L greater than 10% may have a duration of delivery of aboutone month and a depot composition having a terpolymer of CL/G/L with Gless than 50% and L less than 10% may have a duration months up to sixmonths. In general, increasing the G content relative to the CL contentshortens the duration of delivery whereas increasing the CL contentrelative to the G content lengthens the duration of delivery. Thus,among other things, depot compositions having a blend of polymers havingdifferent molecular weights, end groups and comonomer ratios can be usedto create a depot formulation having a lower initial burst and aregulated duration of delivery.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfate,sodium bisulfate, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. If the depot is to be placed inthe spinal area, in various embodiments, the depot may comprise sterilepreservative free material.

The depot can be different sizes, shapes and configurations. There areseveral factors that can be taken into consideration in determining thesize, shape and configuration of the drug depot. For example, both thesize and shape may allow for ease in positioning the drug depot at thetarget tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a cylinder such as a rod or fiber, a flat surfacesuch as a disc, film or sheet (e.g., ribbon-like) or the like.Flexibility may be a consideration so as to facilitate placement of thedrug depot. In various embodiments, the drug depot can be differentsizes, for example, the drug depot may be a length of from about 0.5 mmto 5 mm, or 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, 4.0 mm, 4.5mm and have a diameter of from about 0.01 to about 4 mm, for example,0.25 mm, 0.5 mm, 0.75 mm, or 1.0 mm, 1.25 mm, 1.5 mm, 1.75 mm, 2.0 mm,2.5 mm, 3.0 mm, 3.5 mm, or 4.0 mm. In various embodiments, as thediameter decreases, the surface area that comes in contact with thebodily fluid of the depot increases and therefore release of the drugfrom the depot increases. In various embodiments, the drug depot mayhave a layer thickness of from about 0.005 to 1.0 mm, such as, forexample, from 0.05 to 0.75 mm.

FIG. 2 illustrates a front view of a joint capsule showing percutaneousinjections of the medical device (a drug depot containing a statin) intoor around a hematoma at an early stage of fracture healing in longbones. In this embodiment, a plurality of drug depots are implanted viacannula to the hematoma near the fracture site bilaterally. The drugdepots have polymers that will degrade and release the statin and bedelivered to the fracture site by the vasculature. The statin will causeincrease in bone morphogenic protein and an increase of at leastprogenitor, and/or bone cells at, near or in the bone defect so thathealing of the fracture site will be enhanced.

In some embodiments, an implantable medical device is provided where themedical device releases about 1 mg to about 200 mg of the statin overbetween about 2 to about 4 weeks. In some embodiments, an implantablemedical device is provided where the medical device releases about 0.05mg to about 5 mg per day of the statin. In some embodiments, animplantable medical device is provided where the statin is in themedical device in an amount of from 0.1 mg/cc to 100 mg/cc.

Method of Making Depots

In various embodiments, the drug depot comprising the statin can be madeby combining a biocompatible polymer and a therapeutically effectiveamount of statin or pharmaceutically acceptable salt thereof and formingthe implantable drug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: an statin and other therapeuticagent(s) and other optional additives such as radiographic agent(s),etc. in dissolved or dispersed form. This results in a polymeric matrixregion containing these species after solvent removal. In otherembodiments, a solution containing solvent with dissolved or dispersedtherapeutic agent is applied to a pre-existing polymeric region, whichcan be formed using a variety of techniques including solutionprocessing and thermoplastic processing techniques, whereupon thetherapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: statin,optional additional therapeutic agent(s), radiographic agent(s), and soforth. The resulting mixture is then shaped into an implantable drugdepot. The mixing and shaping operations may be performed using any ofthe conventional devices known in the art for such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, statin may undergo substantial degradationunder ordinary thermoplastic processing conditions. Hence, processing ispreferably performed under modified conditions, which prevent thesubstantial degradation of the therapeutic agent(s). Although it isunderstood that some degradation may be unavoidable during thermoplasticprocessing, degradation is generally limited to 10% or less. Among theprocessing conditions that may be controlled during processing to avoidsubstantial degradation of the therapeutic agent(s) are temperature,applied shear rate, applied shear stress, residence time of the mixturecontaining the therapeutic agent, and the technique by which thepolymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the statin containing drug depot. Conversely, inanother embodiment, the biocompatible polymer can be precompounded withthe therapeutic agent under conditions of reduced temperature andmechanical shear. This precompounded material is then mixed with, forexample, a radio-opacifying agent, also under conditions of reducedtemperature and mechanical shear, and the resulting mixture is shapedinto the drug depot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear (e.g., statin), in variousembodiments, the PGLA or PLA can be premixed with the radio-opacifyingagent at temperatures of about, for example, 150° C. to 170° C. Thetherapeutic agent is then combined with the premixed composition andsubjected to further thermoplastic processing at conditions oftemperature and mechanical shear that are substantially lower than istypical for PGLA or PLA compositions. For example, where extruders areused, barrel temperature, volumetric output are typically controlled tolimit the shear and therefore to prevent substantial degradation of thetherapeutic agent(s). For instance, the therapeutic agent and premixedcomposition can be mixed/compounded using a twin screw extruder atsubstantially lower temperatures (e.g., 100-105° C.), and usingsubstantially reduced volumetric output (e.g., less than 30% of fullcapacity, which generally corresponds to a volumetric output of lessthan 200 cc/min). It is noted that this processing temperature is wellbelow the melting points of statin because processing at or above thesetemperatures will result in substantial therapeutic agent degradation.It is further noted that in certain embodiments, the processingtemperature will be below the melting point of all bioactive compoundswithin the composition, including the therapeutic agent. Aftercompounding, the resulting depot is shaped into the desired form, alsounder conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet) is cooled. Examples of cooling processesinclude air cooling and/or immersion in a cooling bath. In someembodiments, a water bath is used to cool the extruded depot. However,where a water-soluble therapeutic agent such as statin are used, theimmersion time should be held to a minimum to avoid unnecessary loss oftherapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.Otherwise, the water or moisture exposure will allow the drug tocrystallize on the depot and there will be an initial burst effect.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, statin is used and mixed orsprayed with the PLGA or PEG550 polymer, and the resulting depot may beformed by extrusion and dried.

In various embodiments, there is a pharmaceutical formulationcomprising: statin, wherein the statin comprises from about 0.1 wt. % toabout 50 wt. % of the formulation, and at least one biodegradablepolymer. In some embodiments, the statin comprises from about 3 wt. % toabout 20 wt. % or 30 wt. %, about 3 wt. % to about 18 wt. %, about 5 wt.% to about 15 wt. % or about 7.5 wt. % to about 12.5 wt. % of theformulation. By way of example, when using a 5%-15% statin composition,the mole ratio of statin to polymer would be from approximately 16-53when using an approximately 80 kDalton polymer that has a 267 grams/moleratio. By way of another example, when using a 5%-15% statin base in thecomposition, the mole ratio of statin base to polymer would be fromapproximately 18-61 with a mole mass of 230 g/mol. In some embodiments,the weight ratio will be in the range of 10-50% assuming a target doseanabolic dose of ˜1 mg/d for 14 days.

In some embodiments, the drug depot comprises at least one biodegradablematerial in a wt % of about 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%,92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%,78%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 65%, 60%, 55%, 50%, 45%, 35%,25%, 20%, 15%, 10%, or 5% based on the total weight of the depot and theremainder is active and/or inactive pharmaceutical ingredients.

In some embodiments, the at least one biodegradable polymer comprisespoly(lactic-co-glycolide) (PLGA) or poly(orthoester) (POE) or acombination thereof. The poly(lactic-co-glycolide) may comprise amixture of polyglycolide (PGA) and polylactide and in some embodiments,in the mixture, there is more polylactide than polyglycolide. In variousembodiments there is 100% polylactide and 0% polyglycolide; 95%polylactide and 5% polyglycolide; 90% polylactide and 10% polyglycolide;85% polylactide and 15% polyglycolide; 80% polylactide and 20%polyglycolide; 75% polylactide and 25% polyglycolide; 70% polylactideand 30% polyglycolide; 65% polylactide and 35% polyglycolide; 60%polylactide and 40% polyglycolide; 55% polylactide and 45%polyglycolide; 50% polylactide and 50% polyglycolide; 45% polylactideand 55% polyglycolide; 40% polylactide and 60% polyglycolide; 35%polylactide and 65% polyglycolide; 30% polylactide and 70%polyglycolide; 25% polylactide and 75% polyglycolide; 20% polylactideand 80% polyglycolide; 15% polylactide and 85% polyglycolide; 10%polylactide and 90% polyglycolide; 5% polylactide and 95% polyglycolide;and 0% polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In some embodiments, the at least one biodegradable polymer comprisespoly(D,L-lactide-co-caprolactone), or poly(L-lactide-co-caprolactone) orcopolymers thereof or a combination thereof. The molar ratio ofD,L-lactide or L-lactide to caprolactone in thepoly(D,L-lactide-co-caprolactone), or poly(L-lactide-co-caprolactone) is95% D,L-lactide or L-lactide and 5% caprolactone; 90% D,L-lactide orL-lactide and 10% caprolactone; 85% D,L-lactide or L-lactide and 15%caprolactone; 80% D,L-lactide or L-lactide and 20% caprolactone; 75%D,L-lactide or L-lactide and 25% caprolactone; 70% D,L-lactide orL-lactide and 30% caprolactone; 65% D,L-lactide or L-lactide and 35%caprolactone; 60% D,L-lactide or L-lactide and 40% caprolactone; 55%D,L-lactide or L-lactide and 45% caprolactone; 50% D,L-lactide orL-lactide and 50% caprolactone; 45% D,L-lactide or L-lactide and 55%caprolactone; 40% D,L-lactide or L-lactide and 60% caprolactone; 35%D,L-lactide or L-lactide and 65% caprolactone; 30% D,L-lactide orL-lactide and 70% caprolactone; 25% D,L-lactide or L-lactide and 75%caprolactone; 20% D,L-lactide or L-lactide and 80% caprolactone; 15%D,L-lactide or L-lactide and 85% caprolactone; 10% D,L-lactide orL-lactide and 90% caprolactone; or 5% D,L-lactide or L-lactide and 95%caprolactone or copolymers thereof or combinations thereof. In variousembodiments, the medical device comprises polymers and copolymerscontaining various molar ratios of PEG, lactide, glycolide and/orcaprolactone.

In various embodiments, the drug particle size (e.g., statin) is fromabout 1 to about 25 micrometers, or about 5 to 50 micrometers, however,in various embodiments ranges from about 1 micron to 250 microns may beused.

In some embodiments, at least 75% of the particles have a size fromabout 10 micrometer to about 200 micrometers. In some embodiments, atleast 85% of the particles have a size from about 10 micrometer to about200 micrometers. In some embodiments, at least 95% of the particles havea size from about 10 micrometer to about 200 micrometers. In someembodiments, all of the particles have a size from about 10 micrometerto about 200 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 20 micrometer to about 180 micrometers. In some embodiments, atleast 85% of the particles have a size from about 20 micrometers toabout 180 micrometers. In some embodiments, at least 95% of theparticles have a size from about 20 micrometer to about 180 micrometers.In some embodiments, all of the particles have a size from about 20micrometer to about 180 micrometers.

In some embodiments, the biodegradable polymer comprises at least 50 wt.%, at least 60 wt. %, at least 70 wt. %, at least 80 wt. % of theformulation, at least 85 wt. % of the formulation, at least 90 wt. % ofthe formulation, at least 95 wt. % of the formulation or at least 97 wt.% of the formulation. In some embodiments, the at least onebiodegradable polymer and the statin are the only components of thepharmaceutical formulation.

In some embodiments, there is a pharmaceutical formulation comprising:an statin, wherein the statin is in non-esterified form (does notcontain any ester), and comprises from about 0.1 wt. % to about 30 wt. %of the formulation, and at least one biodegradable polymer, wherein theat least one biodegradable polymer comprises poly(lactide-co-glycolide)(or poly(lactic-co-glycolic acid)) or poly(orthoester) or a combinationthereof, and said at least one biodegradable polymer comprises at least70 wt. % of said formulation.

In some embodiments, there is a pharmaceutical formulation comprising anstatin, wherein the statin is lovastatin and comprises from about 0.1wt. % to about 30 wt. % of the formulation and a polymer comprises atleast 70% of the formulation. In some embodiments, the polymer in thisformulation is polyorthoester.

In some embodiments, the formulation comprises a drug depot thatcomprises a biodegradable polyorthoester. The mechanism of thedegradation process of the polyorthoester can be hydrolytical orenzymatical in nature, or both. In various embodiments, the degradationcan occur either at the surface of the drug depot (heterogeneous orsurface erosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion). Polyorthoester can be obtained from A.P.Pharma, Inc. (Redwood City, Calif.) or through the reaction of abis(ketene acetal) such as3,9-diethylidene-2,4,8,10-tetraoxospiro[5,5]undecane (DETOSU) withsuitable combinations of diol(s) and/or polyol(s) such as1,4-trans-cyclohexanedimethanol and 1,6-hexanediol or by any otherchemical reaction that produces a polymer comprising orthoestermoieties.

In some embodiments, there is a method for treating a bone defect in apatient in need of such treatment, the method comprising administering astatin locally at or near or in the bone defect, the statin beingadministered by local injection every day, every other day, every threedays, every seven days, or every month by one dose, continuously orintermittent doses so as to enhance healing of the bone.

A strategy of triangulation may be effective when administering thesepharmaceutical formulations. Thus, a plurality (at least two, at leastthree, at least four, at least five, at least six, at least seven, etc.)drug depots comprising the pharmaceutical formulations may be placedaround the target tissue site (e.g., bone defect) such that the targettissue site falls within a region that is either between theformulations when there are two, or within an area whose perimeter isdefined by a set of plurality of formulations.

In some embodiments, the statin depot is administered parenterally,e.g., by injection. In some embodiments, the injection is intrathecal,which refers to an injection into the spinal canal (intrathecal spacesurrounding the spinal cord). An injection may also be into a muscle orother tissue. In other embodiments, the statin depot is administered byplacement into an open patient cavity during surgery.

In some embodiments, the drug depot (i) comprises one or more immediaterelease layer(s) that is capable of releasing about 5% to about 20% ofthe statin or pharmaceutically acceptable salts thereof relative to atotal amount of the statin or pharmaceutically acceptable salt thereofloaded in the drug depot over a first period of up to 48 hours and (ii)one or more sustain release layer(s) that is capable of releasing about21% to about 99% of the statin or pharmaceutically acceptable saltthereof relative to a total amount of the statin or pharmaceuticallyacceptable salt thereof loaded in the drug depot over a subsequentperiod of up to 3 days to 21 days.

Statins

The medical device comprises a statin that can be disposed within, onthroughout or in certain regions of the medical device. In someembodiments, the interior of the medical device is loaded with a statinthat functions as a nidus or nest for new bone to deposit and grow.

Statins include one or more compound(s) sharing the capacity tocompetitively inhibit the hepatic enzyme 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. Compounds that inhibit the activity ofHMG CoA reductase can be readily identified by using assays well knownin the art; see, as examples, the assays described or cited in U.S. Pat.No. 4,231,938 at column 6, and in International Patent Publication WO84/02131 at pp. 30-33.

Examples of a useful statin that can be in, on or throughout the matrixinclude, but is not limited to, atorvastatin, simvastatin, pravastatin,cerivastatin, mevastatin (see U.S. Pat. No. 3,883,140, the entiredisclosure is herein incorporated by reference), velostatin (also calledsynvinolin; see U.S. Pat. Nos. 4,448,784 and 4,450,171 these entiredisclosures are herein incorporated by reference), fluvastatin,lovastatin, rosuvastatin and fluindostatin (Sandoz XU-62-320),dalvastain (EP Appln. Publ. No. 738510 A2, the entire disclosure isherein incorporated by reference), eptastatin, pitavastatin, orpharmaceutically acceptable salts thereof or a combination thereof. Invarious embodiments, the statin may comprise mixtures of (+)R and (−)-Senantiomers of the statin. In various embodiments, the statin maycomprise a 1:1 racemic mixture of the statin.

In various embodiments, natural products such as, for example, red yeastrice; Zhitai, Cholestin or Hypocol, and Xuezhikang contain statincompounds that act as HMG CoA reductase inhibitors.

Lovastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, etc.). For example,lovastatin may be obtained from Merck as Mevacor® (see U.S. Pat. No.4,231,938, the entire disclosure is herein incorporated by reference).Suitable pharmaceutically acceptable salts of lovastatin include one ormore compounds derived from bases such as sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts ofatorvastin include lithium, calcium, hemicalcium, sodium, potassium,magnesium, aluminum, ferrous or ferric salts thereof or a combinationthereof.

In various embodiments, the therapeutically effective amount oflovastatin that can be placed in the matrix comprises from about 0.1 mgto about 2000 mg, for example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70mg, 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of lovastatinper day. In various embodiments, dosages of from 10 to 500 mg per daymay be given, which for a normal human adult of approximately 70 kg is adosage of from 0.14 to 7.1 mg/kg of body weight per day. In variousembodiments, the dosage may be, for example from 0.1 to 1.0 mg/kg perday or from about 0.3 mg/kg/day to 3 mg/kg/day or from 40 ng/hr or 0.4mcg/hr or from 6.9 mcg/kg/day to 0.68 mg/kg/day.

Atorvastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, etc.). For example,atorvastatin may be obtained from Pfizer as Lipitor® (see U.S. Pat. No.5,273,995, the entire disclosure is herein incorporated by reference).The pharmaceutically acceptable salts of atorvastatin include one ormore compounds that generally can be derived by dissolving the free acidor the lactone; for example, the lactone, in aqueous or aqueous alcoholsolvent or other suitable solvents with an appropriate base andisolating the salt by evaporating the solution or by reacting the freeacid or lactone.

Suitable pharmaceutically acceptable salts of atorvastatin include oneor more compounds derived from bases, such as for example, sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts ofatorvastin include lithium, calcium, hemicalcium, magnesium, zinc,sodium, potassium, magnesium, aluminum, ferrous or ferric salts thereofor a combination thereof.

In various embodiments, the therapeutically effective amount ofatorvastatin that can be placed in the matrix comprises from about 0.1mg to about 2000 mg, for example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70mg, 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of atorvastatinper day. In various embodiments, dosages of from 10 to 500 mg per daymay be given, which for a normal human adult of approximately 70 kg is adosage of from 0.14 to 7.1 mg/kg of body weight per day. In variousembodiments, the dosage may be, for example from 0.1 to 1.0 mg/kg perday or from about 0.3 mg/kg/day to 3 mg/kg/day.

Simvastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, etc.). For example,simvastatin may be obtained from Merck as Zocor® (see U.S. Pat. No.4,444,784, the entire disclosure is herein incorporated by reference).The pharmaceutically acceptable salts of simvastatin include thoseformed from cations such as, for example, sodium, potassium, aluminum,calcium, lithium, magnesium, zinc or tetramethylammonium as well asthose salts formed from amines such as, for example, ammonia,ethylenediamine, N-methylglucamine, lysine, arginine, ornithine,choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, or tris(hydroxymethyl)aminomethane or a combination thereof.

In various embodiments, the therapeutically effective amount ofsimvastatin in the matrix comprises from about 0.1 mg to about 2000 mg,for example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, or 100 mg of simvastatin per day. In variousembodiments, dosages of from 10 to 500 mg per day may be given, whichfor a normal human adult of approximately 70 kg is a dosage of from 0.14to 7.1 mg/kg of body weight per day. In various embodiments, the dosagemay be, for example from 0.1 to 1.0 mg/kg per day or from about 0.3mg/kg/day to 3 mg/kg/day.

In various embodiments, the therapeutically effective amount ofmevastatin in the matrix comprises from about 0.1 mg to about 2000 mg,for example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, or 100 mg of mevastatin per day. In variousembodiments, dosages of from 10 to 500 mg per day may be given, whichfor a normal human adult of approximately 70 kg is a dosage of from 0.14to 7.1 mg/kg of body weight per day. In various embodiments, the dosagemay be, for example from 0.1 to 1.0 mg/kg per day or from about 0.3mg/kg/day to 3 mg/kg/day.

Pravastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, liquid, etc.). For example,pravastatin may be obtained from Bristol-Myers Squibb as Pravachol® (seeU.S. Pat. No. 4,346,227, the entire disclosure is herein incorporated byreference). Suitable pharmaceutically acceptable salts of pravastatininclude one or more compounds derived from bases or acids, such as forexample, sodium hydroxide, potassium hydroxide, lithium hydroxide,calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol, magnesiumhydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferrichydroxide, ammonium hydroxide, hydroxy-carboxylic acids or organicamines such as N-methylglucamine, choline, arginine or the like oresters of the hydroxy-carboxylic acids of pravastatin or a combinationthereof. Suitable pharmaceutically acceptable salts of pravastatininclude lithium, calcium, hemicalcium, magnesium, zinc, sodium,potassium, magnesium, aluminum, ferrous or ferric salts thereof acombination thereof.

In various embodiments, the therapeutically effective amount ofpravastatin in the matrix comprises from about 0.1 mg to about 2000 mg,for example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, or 100 mg of pravastatin per day. In variousembodiments, dosages of from 10 to 500 mg per day may be given, whichfor a normal human adult of approximately 70 kg is a dosage of from 0.14to 7.1 mg/kg of body weight per day. In various embodiments, the dosagemay be, for example from 0.1 to 1.0 mg/kg per day or from about 0.3mg/kg/day to 3 mg/kg/day.

Cerivastatin (also known as rivastatin) is a statin that may be obtainedfrom various manufacturers in various forms (e.g., injection, powder,liquid, etc.). For example, cerivastatin may be obtained from Bayer AGas Baychol® (see U.S. Pat. No. 5,502,199, the entire disclosure isherein incorporated by reference). Suitable pharmaceutically acceptablesalts of cerivastatin include one or more compounds derived from bases,such as for example, sodium hydroxide, potassium hydroxide, lithiumhydroxide, calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol,magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous orferric hydroxide, ammonium hydroxide or organic amines such asN-methylglucamine, choline, arginine or the like or combinationsthereof. Suitable pharmaceutically acceptable salts of cerivastatininclude lithium, calcium, hemicalcium, magnesium, zinc, sodium,potassium, magnesium, aluminum, ferrous or ferric salts thereof or acombination thereof.

In various embodiments, the therapeutically effective amount ofcerivastatin in the matrix comprises from about 0.1 mg to about 2000 mg,for example, 0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, or 100 mg of cerivastatin per day. In variousembodiments, dosages of from 10 to 500 mg per day may be given, whichfor a normal human adult of approximately 70 kg is a dosage of from 0.14to 7.1 mg/kg of body weight per day. In various embodiments, the dosagemay be, for example from 0.1 to 1.0 mg/kg per day or from about 0.3mg/kg/day to 3 mg/kg/day.

Fluvastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, liquid, etc.). For example,fluvastatin may be obtained from Novartis Pharmaceuticals as Lescol®(see U.S. Pat. No. 5,354,772, the entire disclosure is hereinincorporated by reference). Some examples, of pharmaceuticallyacceptable salts include, for example, pharmaceutically acceptable saltsof phosphoric acid such as tribasic calcium phosphate or inorganiccarbonate and bicarbonate salts, e.g., sodium carbonate, sodiumbicarbonate, calcium carbonate, or mixtures thereof. Suitablepharmaceutically acceptable salts of fluvastatin include lithium,calcium, hemicalcium, magnesium, zinc, sodium, potassium, magnesium,aluminum, ferrous or ferric salts thereof or a combination thereof.

In various embodiments, the therapeutically effective amount offluvastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of fluvastatin per day. For example, the dose maybe 0.1 to 10 mg/kg of body weight.

Rosuvastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, liquid, etc.). For example,rosuvastatin may be obtained from AstraZeneca as Crestor® (See U.S. Pat.Nos. 6,316,460, 6,858,618, and RE37314, the entire disclosures areherein incorporated by reference). Suitable pharmaceutically acceptablesalts of rosuvastatin include one or more compounds derived from bases,such as for example, sodium hydroxide, potassium hydroxide, lithiumhydroxide, calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol,magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous orferric hydroxide, ammonium hydroxide or organic amines such asN-methylglucamine, choline, arginine or the like or combinationsthereof. Suitable pharmaceutically acceptable salts of rosuvastatininclude lithium, calcium, hemicalcium, tribasic calcium phosphate,magnesium, zinc, sodium, potassium, magnesium, aluminum, ferrous orferric salts thereof or a combination thereof.

In various embodiments, the therapeutically effective amount ofrosuvastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of rosuvastatin per day. In various embodiments,dosages of from 10 to 500 mg per day may be given, which for a normalhuman adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kgof body weight per day. In various embodiments, the dosage may be, forexample from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day.

Pitavastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, liquid, etc.). Suitablepharmaceutically acceptable salts of pitavastatin include one or morecompounds derived from bases, such as for example, sodium hydroxide,potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts ofpitavastatin include lithium, calcium, hemicalcium, tribasic calciumphosphate, magnesium, zinc, sodium, potassium, magnesium, aluminum,ferrous or ferric salts thereof or a combination thereof.

In various embodiments, the dosage of pitavastatin can be between 1 to100 mg/day for example 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg,40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, or 100 mg of pitavastatin. In various embodiments,pitavastatin may be given at a dose of, for example, from 0.1 to 1.0mg/kg per day or from about 0.3 mg/kg/day to 3 mg/kg/day.

Eptastatin, velostatin, fluindostatin, or dalvastain are statins thatmay be obtained from various manufacturers in various forms (e.g.,injection, powder, liquid, etc.). Suitable pharmaceutically acceptablesalts of eptastatin, velostatin, fluindostatin, or dalvastain includeone or more compounds derived from bases, such as for example, sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts ofeptastatin, velostatin, fluindostatin, or dalvastain include lithium,calcium, hemicalcium, tribasic calcium phosphate, magnesium, zinc,sodium, potassium, magnesium, aluminum, ferrous or ferric salts thereofor a combination thereof.

In various embodiments, the dosage of eptastatin, velostatin,fluindostatin, or dalvastain can be between 1 to 100 mg/day for example5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or100 mg of eptastatin velostatin, fluindostatin, or dalvastain. Invarious embodiments, eptastatin may be given at a dose of, for example,from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day.

The statin may be incorporated directly into the medical device.Alternatively, the statin may be incorporated into polymeric ornon-polymeric material, as well as synthetic or naturally occurringmaterial (as discussed above) and formed into capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsand then applied in or to the matrix. Suitable materials forincorporating the statin are pharmaceutically acceptable biodegradableand/or any bioabsorbable materials that are preferably FDA approved orGRAS materials.

In some embodiments, the nanoparticles will generally be in the range ofabout 1 to 50, more usually 5 to 25 nm, with the distribution asindicated above. In some embodiments, the microparticles will generallybe in the range of about 1 to 200 micrometers, more usually in the rangeof about 5 to 100 micrometers with the distribution as indicated above.Only a few large particles can unduly distort the weight/sizedistribution. It should be understood that in the event of a fewoutliers the numbers given may be somewhat off and such outliers shouldnot be considered in the distribution, as they generally will not exceed10 weight % of the composition and will be at least about 1.5 timesgreater than the largest particle coming within the distribution.

In some embodiments, a statin and/or other therapeutic agent may bedisposed on or in the matrix by hand, electrospraying, ionizationspraying or impregnating, vibratory dispersion (including sonication),nozzle spraying, compressed-air-assisted spraying, injecting, brushingand/or pouring. For example, a statin such as lovastatin may be disposedon or in the biodegradable matrix by the surgeon before thebiodegradable matrix is administered or the matrix may be pre-loadedwith the statin by the manufacturer beforehand.

The statin may contain inactive materials such as buffering agents andpH adjusting agents such as potassium bicarbonate, potassium carbonate,potassium hydroxide, sodium acetate, sodium borate, sodium bicarbonate,sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfate,sodium bisulfate, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. In some embodiments, the statinmay comprise sterile and/or preservative free material.

These above inactive ingredients may have multi-functional purposesincluding the carrying, stabilizing and controlling the release of thestatin and/or other therapeutic agent(s). The sustained release process,for example, may be by a solution-diffusion mechanism or it may begoverned by an erosion-sustained process.

In some embodiments, a pharmaceutically acceptable formulationcomprising a statin is provided, wherein the formulation is afreeze-dried or lyophilized formulation containing the matrix.Typically, in the freeze-dried or lyophilized formulation an effectiveamount of a statin is provided. Lyophilized formulations can bereconstituted into solutions, suspensions, emulsions, or any othersuitable form for administration or use. The lyophilized formulation maycomprise the liquid used to reconstitute the statin. Lyophilizedformulations are typically first prepared as liquids, then frozen andlyophilized. The total liquid volume before lyophilization can be less,equal to, or more than the final reconstituted volume of the lyophilizedformulation. The lyophilization process is well known to those ofordinary skill in the art, and typically includes sublimation of waterfrom a frozen formulation under controlled conditions.

Lyophilized formulations can be stored at a wide range of temperatures.Lyophilized formulations may be stored at or below 30° C., for example,refrigerated at 4° C., or at room temperature (e.g., approximately 25°C.).

Lyophilized formulations of the statin are typically reconstituted foruse by addition of an aqueous solution to dissolve the lyophilizedformulation. A wide variety of aqueous solutions can be used toreconstitute a lyophilized formulation. In some embodiments, lyophilizedformulations can be reconstituted with a solution containing water(e.g., USP WFI, or water for injection) or bacteriostatic water (e.g.,USP WFI with 0.9% benzyl alcohol). However, solutions comprising buffersand/or excipients and/or one or more pharmaceutically acceptable carriescan also be used. In some embodiments, the solutions do not contain anypreservatives (e.g., are preservative free).

Application of the Statin to the Matrix

In some embodiments, a therapeutic agent (including one or more statins)may be disposed on or in the interior of the matrix by hand,electrospraying, ionization spraying or impregnating, vibratorydispersion (including sonication), nozzle spraying,compressed-air-assisted spraying, injecting, brushing and/or pouring.

Application of the statin to the matrix may occur at the time of surgeryor by the manufacturer or in any other suitable manner. For example, thestatin may be further reconstituted using a syringe and the syringe canbe placed into the interior of the matrix via insertion of a needle orcannula (piercing the matrix) and placing it into the interior of thematrix and injecting the statin so it is evenly distributed throughoutthe porous interior.

In some embodiments, the statin may be applied to the matrix (i.e.,collagen) prior to combining the materials and forming it into the finalmatrix shape. Indeed, the statin can be blended into the natural orsynthetic polymer (i.e., POE) and poured into molds of the final shapeof the matrix. Alternatively, the statin, such as lovastatin, can beincorporated in a suitable liquid carrier, and applied onto and/or intothe porous loaded matrix after forming it into the final shape bysoaking, dripping, injecting, spraying, etc. or the matrix can be moldedinto the desired shape.

In some embodiments, the lyophilized statin can be disposed in a vial bythe manufacturer and then the surgeon can mix the diluent with thelyophilized statin. The matrix then can be parenterally administered tothe target tissue site. The term “parenteral” as used herein refers tomodes of administration which bypass the gastrointestinal tract, andinclude for example, intramuscular, intraperitoneal, intrasternal,subcutaneous, intra-operatively, intravenously, intrathecally,intradiscally, peridiscally, epidurally, perispinally, intraarticular orcombinations thereof.

In some embodiments, the statin is supplied in a liquid carrier (e.g.,an aqueous buffered solution). Exemplary aqueous buffered solutionsinclude, but are not limited to, TE, HEPES(2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid), MES(2-morpholinoethanesulfonic acid), sodium acetate buffer, sodium citratebuffer, sodium phosphate buffer, a Tris buffer (e.g., Tris-HCL),phosphate buffered saline (PBS), sodium phosphate, potassium phosphate,sodium chloride, potassium chloride, glycerol, calcium chloride or acombination thereof. In various embodiments, the buffer concentrationcan be from about 1 mM to 100 mM.

Additional Therapeutic Agents

The statins of the present application may be disposed on or in thematrix with other therapeutic agents. For example, the statin may bedisposed on or in the carrier by electrospraying, ionization spraying orimpregnating, vibratory dispersion (including sonication), nozzlespraying, compressed-air-assisted spraying, brushing and/or pouring.

Exemplary therapeutic agents include but are not limited to IL-1inhibitors, such Kineret® (anakinra), which is a recombinant,non-glycosylated form of the human interleukin-1 receptor antagonist(IL-1Ra), or AMG 108, which is a monoclonal antibody that blocks theaction of IL-1. Therapeutic agents also include excitatory amino acidssuch as glutamate and aspartate, antagonists or inhibitors of glutamatebinding to NMDA receptors, AMPA receptors, and/or kainate receptors.Interleukin-1 receptor antagonists, thalidomide (a TNF-α releaseinhibitor), thalidomide analogues (which reduce TNF-α production bymacrophages), quinapril (an inhibitor of angiotensin II, whichupregulates TNF-α), interferons such as IL-11 (which modulate TNF-αreceptor expression), and aurin-tricarboxylic acid (which inhibitsTNF-α), may also be useful as therapeutic agents for reducinginflammation. It is further contemplated that where desirable apegylated form of the above may be used. Examples of still othertherapeutic agents include NF kappa B inhibitors such as antioxidants,such as dithiocarbamate, and other compounds, such as, for example,sulfasalazine.

Examples of therapeutic agents suitable for use also include, but arenot limited to, an anti-inflammatory agent, analgesic agent, orosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, apazone, celecoxib, diclofenac,diflunisal, enolic acids (piroxicam, meloxicam), etodolac, fenamates(mefenamic acid, meclofenamic acid), gold, ibuprofen, indomethacin,ketoprofen, ketorolac, nabumetone, naproxen, nimesulide, salicylates,sulfasalazine[2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid, sulindac, tepoxalin, and tolmetin; as well as antioxidants, suchas dithiocarbamate, steroids, such as cortisol, cortisone,hydrocortisone, fludrocortisone, prednisone, prednisolone,methylprednisolone, triamcinolone, betamethasone, dexamethasone,beclomethasone, fluticasone or a combination thereof.

Suitable analgesic agents include, but are not limited to,acetaminophen, bupivicaine, fluocinolone, lidocaine, opioid analgesicssuch as buprenorphine, butorphanol, dextromoramide, dezocine,dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil,hydrocodone, hydromorphone, ketobemidone, levomethadyl, mepiridine,methadone, morphine, nalbuphine, opium, oxycodone, papaveretum,pentazocine, pethidine, phenoperidine, piritramide, dextropropoxyphene,remifentanil, tilidine, tramadol, codeine, dihydrocodeine, meptazinol,dezocine, eptazocine, flupirtine, amitriptyline, carbamazepine,gabapentin, pregabalin, or a combination thereof.

The therapeutic agent in the device may include, but is not limited to,members of the fibroblast growth factor family, including acidic andbasic fibroblast growth factor (FGF-1 and FGF-2) and FGF-4, members ofthe platelet-derived growth factor (PDGF) family, including PDGF-AB,PDGF-BB and PDGF-AA; EGFs; the TGF-β superfamily, including TGF-β1, 2 or3; osteoid-inducing factor (OIF); angiogenin(s); endothelins; hepatocytegrowth factor or keratinocyte growth factor; members of the bonemorphogenetic proteins (BMP's) BMP-1, BMP-3, BMP-2; OP-1, BMP-2A,BMP-2B, or BMP-7; HBGF-1 or HBGF-2; growth differentiation factors(GDF's); members of the hedgehog family of proteins, including indian,sonic and desert hedgehog; ADMP-1; other members of the interleukin (IL)family; or members of the colony-stimulating factor (CSF) family,including CSF-1, G-CSF, and GM-CSF, or isoforms thereof; or VEGF, NELL-1(neural epidermal growth factor-like 1), CD-RAP (cartilage-derivedretinoic acid-sensitive protein) or combinations thereof.

In some embodiments, the device comprises osteogenic proteins. Exemplaryosteogenic proteins include, but are not limited to, OP-1, OP-2, OP-3,BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11,BMP-12, BMP-13, BMP-14, BMP-15, GDF-1, GDF-2, GDF-3, GDF-5, GDF-6,GDF-7, GDF-8, GDF-9, GDF-10, GDF-11, GDF-12, CDMP-1, CDMP-2, CDMP-3,DPP, Vg-1, Vgr-1, 60A protein, NODAL, UNIVIN, SCREW, ADMP, NEURAL, andTGF-beta. As used herein, the terms “morphogen,” “bone morphogen,”“BMP,” “osteogenic protein” and “osteogenic factor” embrace the class ofproteins typified by human osteogenic protein 1 (hOP-1).

Exemplary growth factors include, but are not limited to, members of thetransforming growth factor beta family, including bone morphogeneticprotein 2 (BMP-2); bone morphogenetic protein 4 (BMP-4); andtransforming growth factors beta-1, beta-2, and beta-3 (potentkeratinocyte growth factors). Other useful members of the transforminggrowth factor beta family include BMP-3, BMP-5, BMP-6, BMP-9, DPP, Vg1,Vgr, 60A protein, GDF-1, GDF-3, GDF-5, GDF-6, GDF-7, CDMP-1, CDMP-2,CDMP-3, BMP-10, BMP-11, BMP-13, BMP-15, Univin, Nodal, Screw, ADMP,Neural, and amino acid sequence variants thereof. Other growth factorsinclude epidermal growth factor (EGF), which induces proliferation ofboth mesodermal and ectodermal cells, particularly keratinocytes andfibroblasts; platelet-derived growth factor (PDGF), which exertsproliferative effects on mesenchymal cells; fibroblast growth factor(FGF), both acidic and basic; and insulin-like growth factor 1 (IGF-1)or 2 (IGF-2), which mediate the response to growth hormone, particularlyin bone growth. Further growth factors include osteogenic proteins. Aparticularly preferred osteogenic protein is OP-1, also known as bonemorphogenetic protein 7 (BMP-7). OP-1 is a member of the transforminggrowth factor beta gene superfamily.

Kits

The matrix, statin and devices to administer the implantable matrixcomposition may be sterilizable. In various embodiments, one or morecomponents of the matrix, and/or medical device to administer it may besterilizable by radiation in a terminal sterilization step in the finalpackaging. Terminal sterilization of a product provides greaterassurance of sterility than from processes such as an aseptic process,which require individual product components to be sterilized separatelyand the final package assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In some embodiments, the implantable matrix may be packaged in amoisture resistant package and then terminally sterilized by gammairradiation. In use the surgeon removes the one or all components fromthe sterile package for use.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the matrix. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity.

Other methods may also be used to sterilize the implantable matrixand/or one or more components of the matrix, including, but not limitedto, gas sterilization, such as, for example, with ethylene oxide orsteam sterilization.

In various embodiments, a kit is provided comprising the statin, matrix,and/or diluents. The kit may include additional parts along with theimplantable matrix combined together to be used to implant the matrix(e.g., wipes, needles, syringes, etc.). The kit may include the matrixin a first compartment. The second compartment may include a vialholding the statin, diluent and any other instruments needed for thelocalized drug delivery. A third compartment may include gloves, drapes,wound dressings and other procedural supplies for maintaining sterilityof the implanting process, as well as an instruction booklet, which mayinclude a chart that shows how to implant the matrix afterreconstituting the statin. A fourth compartment may include additionalneedles and/or sutures. Each tool may be separately packaged in aplastic pouch that is radiation sterilized. A fifth compartment mayinclude an agent for radiographic imaging. A cover of the kit mayinclude illustrations of the implanting procedure and a clear plasticcover may be placed over the compartments to maintain sterility.

EXAMPLES

These examples show the trend that all the statin formulations enhancedmechanical strength of fractured bone.

Three formulations of lovastatin were tested in the standard rat femoralfracture model. The three formulations were compared to a placebocontrol that did not contain lovastatin. The following formulations wereinjected or implanted locally next to the femoral fracture and tests atthe fracture site were conduct four weeks after the injection orimplantation of the drug depot: 1) 50:50 DLG having a inherent viscosityof 0.34 and an acid end cap on the polymer, where the formulation was ina depot form (e.g., drug pellet) that had 15% and 55 wt. % drug loadswith lovastatin; 2) injectable hardening gel with 1 wt. % drug load, thegel comprises N-Methyl-2-pyrrolidone (NMP) and hardened afteradministration. The gel released 5 wt. % of the lovastatin within 24hours and 45 wt % of the drug load within 4 weeks; and 3) microspherewith 100 wt % lovastatin was administered locally by injection, themicrospheres contained 25 wt. % PEG 400 and 75 wt. % hyaluronic acid asthe delivery vehicle. The particle size of the lovastatin was on average70 microns.

The test articles were delivered to the fracture site at the time ofinjury. The non-treated (control) and treated bone was collected fourweeks post treatments, and subjected to three-point bending test ofmechanical strength. The data are shown as the percentage increase inmaximum load (breaking force) in comparison to control (mean±S.D.).

FIG. 3 is a bar graph illustration of the percentage increase in maximumload to rat femoral fractures for different formulations of lovastatincompared to a control that did not contain lovastatin. The drug depotloaded with 15% lovastatin had the most consistent efficacy at thelowest total dose delivered over the four-week period. The drug depothaving the 15% lovastatin drug load used was less irritating to thetissue as compared to the microspheres and the gel. The drug depotloaded with 55% lovastatin had the next most consistent efficacy at a 9times higher dose than that of 15% lovastatin. The lovastatinmicrospheres, which contained 100% lovastatin had the next mostconsistent efficacy at an 18 times higher dose than that of 15%lovastatin. The drug depot in gel form that was loaded with 1%lovastatin had the least consistent efficacy at a twice higher dose thanthat of 15% lovastatin as shown in FIG. 3. In some embodiments, thedaily dose of lovastatin per day for humans can be from 10 mcg to 100mcg/day or 25 mcg to 30 mcg to 50 mcg to 60 mcg to 70 mcg to 80 mcg to90 mcg to 100 mcg per day or from about 1 mg-20 mg over the 4 weekperiod, which is considerably lower than the oral dosages (e.g., 10mg-80 mg per day) of lovastatin for treatment of high serum cholesterol

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

1. An implantable medical device configured to fit at, near or in a bonedefect, the medical device comprising a biodegradable polymer and atherapeutically effective amount of a statin disposed throughout themedical device, wherein the medical device allows influx of at leastprogenitor, and/or bone cells at, near or in the bone defect.
 2. Animplantable medical device according to claim 1, wherein the medicaldevice comprises a drug depot capable of releasing an effective amountof a statin to facilitate bone formation within the bone defect.
 3. Animplantable medical device according to claim 2, wherein the drug depotcomprises a gel.
 4. An implantable medical device according to claim 1,wherein the medical device comprises an osteoconductive matrix.
 5. Animplantable medical device according to claim 4, wherein theosteoconductive matrix comprises mineral particles dispersed therein. 6.An implantable medical device according to claim 1, wherein the statincomprises at least cerivastatin, atorvastatin, simvastatin, pravastatin,fluvastatin, lovastatin, rosuvastatin, eptastatin, pitavastatin,velostatin, fluindostatin, dalvastain, or pharmaceutically acceptablesalts thereof or a combination thereof and the matrix is freeze driedand rehydrated at the time of use.
 7. An implantable medical deviceaccording to claim 3, wherein the gel is a hardening gel.
 8. Animplantable medical device according to claim 1, wherein the medicaldevice has a volume of about 1 ml to about 5 ml.
 9. An implantablemedical device according to claim 1, wherein the medical device releasesabout 1 mg to about 200 mg of the statin over between about 2 to about 4weeks.
 10. An implantable medical device according to claim 1, whereinthe medical device releases about 0.05 mg to about 10 mg per day of thestatin or 1 mg to 20 mg over at least 4 weeks.
 11. An implantablemedical device according to claim 1, wherein the statin is in themedical device in an amount of from 0.1 mg/cc to 100 mg/cc.
 12. Animplantable medical device according to claim 1, wherein (i) the medicaldevice releases 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% of the statinloaded in the medical device over a period of 3 to 6 weeks after thedevice is administered thereto; (ii) the statin is encapsulated inmicroparticles, microspheres, microcapsules, and/or microfibers anddistributed in the medical device; and (iii) the statin is encapsulatedin nanoparticles, nanospheres, nanocapsules, and/or nanofibers anddistributed in the medical device.
 13. An implantable medical deviceaccording to claim 5, wherein the mineral particles comprise a cortical,cancellous, corticocancellous, allogenic, xenogenic or transgenic bonetissue, bone powder, demineralized bone powder, porous calcium phosphateceramics, hydroxyapatite, tricalcium phosphate, bioactive glass or acombination thereof.
 14. An implantable medical device according toclaim 13, wherein (i) the mineral particles comprise tricalciumphosphate and hydroxyapatite in a ratio of about 70:30 to about 90:10 or(ii) the mineral particles comprise tricalcium phosphate andhydroxyapatite in a ratio of about 85:15; or (iii) the mineral particlesrepresent at least 50 to 98 weight percent of the medical device.
 15. Animplantable medical device according to claim 2, wherein the drug depotcomprises (i) one or more immediate release surfaces that has a burstrelease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% of the statinover 24 hours or 48 hours at, near or in the bone defect and (ii) one ormore sustain release surfaces that releases an effective amount of thestatin over a subsequent period of 3 to 6 weeks.
 16. A method oftreating a bone defect in which the bone defect site possesses at leastone cavity, the method comprising inserting an implantable medicaldevice at, near or in the defect site, the implantable medical devicecomprising a biodegradable polymer and a therapeutically effectiveamount of a statin disposed throughout the medical device, wherein themedical device allows influx of at least progenitor, and/or bone cellsat, near or in the bone defect.
 17. A method of treating a bone defectaccording to claim 16, wherein the bone defect is a fracture.
 18. Amethod of treating a bone defect according to claim 16, wherein themedical device is used in conjunction with an internal fixation device.19. A method of treating a bone defect according to claim 16, whereinthe medical device comprises a growth factor.
 20. A method of treating abone defect according to claim 16, wherein the medical device comprisesa drug depot.